Prednisolone has a positive effect on the kidney but not on the liver of brain dead rats: a potencial role in complement activation

Journal of Translational Medicine

Henri GD Leuvenink⁴  Rutger J Ploeg¹  Jian-ning Zhang²  Petra J Ottens⁴  Mohammed Z Akhtar¹  Bo Liu²  Rolando Rebolledo³ 

[1] Nuffield Department of Surgical Sciences, University of Oxford, Headington, OX3 9DU Oxford, UK;Department of Neurosurgery, Tianjin Medical University General Hospital, 154 Anshan Road, 300052 Tianjin, China;Department of Surgery, Faculty of Medicine, University of Chile, Independencia 1027, 8380453 Santiago, Chile;Department of Surgery, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

关键词: Liver transplantation;    Kidney transplantation;    Prednisolone;    Steroids;    Organ donation;    Brain death;   

Others  :  814214
DOI  :  10.1186/1479-5876-12-111

 received in 2014-02-13, accepted in 2014-04-25,  发布年份 2014

【 摘 要 】

Background

Contradictory evidence has been published on the effects of steroid treatments on the outcomes of kidney and liver transplantation from brain dead (BD) donors. Our study aimed to evaluate this disparity by investigating the effect of prednisolone administration on BD rats.

Methods

BD induction was performed in ventilated rats by inflating a Fogarty catheter placed in the epidural space. Prednisolone (22.5 mg/kg) was administered 30 min prior to BD induction. After four hours of determination of BD: serum, kidney and liver tissues samples were collected and stored. RT-qPCR, routine biochemistry and immunohistochemistry were performed.

Results

Prednisolone treatment reduced circulating IL-6 and creatinine plasma levels but not serum AST, ALT or LDH. Polymorphonuclear influx assessed by histology, and inflammatory gene expression were reduced in the kidney and liver. However, complement component 3 (C3) expression was decreased in kidney but not in liver. Gene expression of HSP-70, a cytoprotective protein, was down-regulated in the liver after treatment.

Conclusions

This study shows that prednisolone decreases inflammation and improves renal function, whilst not reducing liver injury. The persistence of complement activation and the negative effect on protective cellular mechanisms in the liver may explain the disparity between the effects of prednisolone on the kidney and liver of BD rats. The difference in the molecular and cellular responses to prednisolone administration may explain the contradictory evidence of the effects of prednisolone on different organ types from brain dead organ donors.

【 授权许可】

   
2014 Rebolledo et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Bos EM, Leuvenink HGD, van Goor H, Ploeg RJ: Kidney grafts from brain dead donors: Inferior quality or opportunity for improvement? Kidney Int 2007, 72(7):797-805. doi:10.1038/sj.ki.5002400
• [2]Westendorp WH, Leuvenink HG, Ploeg RJ: Brain death induced renal injury. Curr Opin Organ Trans 2011, 16(2):151-156. doi:10.1097/MOT.0b013e328344a5dc
• [3]Terasaki PI, Cecka JM, Gjertson DW, Takemoto S: High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995, 333(6):333-336. doi:10.1056/NEJM199508103330601
• [4]Belzer FO, Southard JH: Principles of solid-organ preservation by cold storage. Transplantation 1988, 45(4):673-676.
• [5]Maathuis M-HJ, Leuvenink HGD, Ploeg RJ: Perspectives in organ preservation. Transplantation 2007, 83(10):1289-1298. doi:10.1097/01.tp.0000265586.66475.cc
• [6]t Hart NA, Van Der Plaats A, Leuvenink HG, Wiersema-Buist J, Olinga P, Van Luyn MJ, Verkerke GJ, Rakhorst G, Ploeg RJ: Initial blood washout during organ procurement determines liver injury and function after preservation and reperfusion. Am J Transplant: Official J Am Soc Transplant Am Soc Transplant Surg 2004, 4(11):1836-1844.
• [7]Wetzel RC, Setzer N, Stiff JL, Rogers MC: Hemodynamic responses in brain dead organ donor patients. Anesth Analg 1985, 64(2):125-128.
• [8]Mascia L, Bosma K, Pasero D, Galli T, Cortese G, Donadio P, Bosco R: Ventilatory and hemodynamic management of potential organ donors: An observational survey*. Crit Care Med 2006, 34(2):321-327. doi:10.1097/01.CCM.0000196828.87358.6E
• [9]Fugate JE, Rabinstein AA, Wijdicks EFM: Blood pressure patterns after brain death. Neurology 2011, 77(4):399-401. doi:10.1212/WNL.0b013e3182270444
• [10]Belzberg H, Shoemaker WC, Wo CCJ, Nicholls TP, Dang ABC, Zelman V, Gruen JP, Berne TV, Demetriades D: Hemodynamic and oxygen transport patterns after head trauma and brain death: implications for management of the organ donor. J Trauma: Inj Infect Crit Care 2007, 63(5):1032-1042. doi:10.1097/01.ta.0000235995.86162.d2
• [11]Howlett TA, Keogh AM, Perry L, Touzel R, Rees LH: Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy. Transplantation 1989, 47(5):828-834.
• [12]Masson F, Latapie MJ, Maurette P, Thicoïpé M: Thyroid function in brain-dead donors. Transplant Int: Official J Eur Soc Organ Transplant 1990, 3(4):226-233.
• [13]Fitzgerald RD, Dechtyar I, Templ E, Pernerstorfer T, Hackl W, Lackner FX: Endocrine stress reaction to surgery in brain-dead organ donors. Transplant Int: Official J Eur Soc Organ Trans 1996, 9(2):102-108.
• [14]Adrie C, Monchi M, Fulgencio J-P, Cottias P, Haouache H, Alvarez-Gonzalvez A, Guerrini P, Cavaillon J. -M, Adib-Conquy M: Immune status and apoptosis activation during brain death. Shock (Augusta, Ga) 2010, 33(4):353-362,. doi:10.1097/SHK.0b013e3181b65b99
• [15]Jassem W, Koo DDH, Cerundolo L, Rela M, Heaton ND, Fuggle SV: Leukocyte infiltration and inflammatory antigen expression in cadaveric and living-donor livers before transplant1. Transplantation 2003, 75(12):2001-2007. doi:10.1097/01.TP.0000061605.30685.03
• [16]Murugan R, Venkataraman R, Wahed AS, Elder M, Hergenroeder G, Carter M, Madden NJ, Powner D, Kellum JA: Increased plasma interleukin-6 in donors is associated with lower recipient hospital-free survival after cadaveric organ transplantation*. Crit Care Med 2008, 36(6):1810-1816. doi:10.1097/CCM.0b013e318174d89f
• [17]Nijboer WN, Schuurs TA, van der Hoeven JAB, Leuvenink HGD, van der Heide JJH, van Goor H, Ploeg RJ: Effects of brain death on stress and inflammatory response in the human donor kidney. Transplant Proc 2005, 37(1):367-369. doi:10.1016/j.transproceed.2004.12.262
• [18]Cooper DK, Novitzky D, Wicomb WN: The pathophysiological effects of brain death on potential donor organs, with particular reference to the heart. Ann R Coll Surg Engl 1989, 71(4):261-266.
• [19]Dictus C, Vienenkoetter B, Esmaeilzadeh M, Unterberg A, Ahmadi R: Critical care management of potential organ donors: our current standard. Clin Transplant 2009, 23(Suppl 21):2-9. doi:10.1111/j.1399-0012.2009.01102.x
• [20]Shemie SD, Ross H, Pagliarello J, Baker AJ, Greig PD, Brand T, Cockfield S, Keshavjee S, Nickerson P, Rao V, Guest C, Young K, Doig C, Group PR: Organ donor management in Canada: recommendations of the forum on Medical Management to Optimize Donor Organ Potential. In Canadian Medical Association Journal. Montréal, Que.: McGill University Health Centre; 2006:13-32. doi:10.1503/cmaj.045131
• [21]Novitzky D, Cooper DKC, Rosendale JD, Kauffman HM: Hormonal therapy of the brain-dead organ donor: experimental and clinical studies. Transplantation 2006, 82(11):1396-1401. doi:10.1097/01.tp.0000237195.12342.f1
• [22]Damman J, Hoeger S, Boneschansker L, Theruvath A, Waldherr R, Leuvenink HG, Ploeg RJ, Yard BA, Seelen MA: Targeting complement activation in brain-dead donors improves renal function after transplantation. Transplant Immunol 2011, 24(4):233-237. doi:10.1016/j.trim.2011.03.001
• [23]Damman J, Daha MR, Van Son WJ, Leuvenink HG, Ploeg RJ, Seelen MA: Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury. Am J Transplant: Official J Am Soc Transplant Am Soc Transplant Surg 2011, 11(4):660-669. doi:10.1111/j.1600-6143.2011.03475.x
• [24]Roskott AMC, Nieuwenhuijs VB, Dijkstra G, Koudstaal LG, Leuvenink HGD, Ploeg RJ: Small bowel preservation for intestinal transplantation: a review. Transplant Int: Official J Eur Soc Organ Transplant 2011, 24(2):107-131. doi:10.1111/j.1432-2277.2010.01187.x
• [25]Koudstaal LG, Ottens PJ, Uges DRA, Ploeg RJ, Van Goor H, Leuvenink HGD: Increased intestinal permeability in deceased brain dead rats. Transplantation 2009, 88(3):444-446. doi:10.1097/TP.0b013e3181af39bd
• [26]Lam L, Inaba K, Branco BC, Putty B, Salim A, Green DJ, Talving P, Demetriades D: The impact of early hormonal therapy in catastrophic brain-injured patients and its effect on organ procurement. Am Surg 2012, 78(3):318-324.
• [27]Nath DS, Basha HI, Liu MH, Moazami N, Ewald GA: Increased recovery of thoracic organs after hormonal resuscitation therapy. HEALUN 2012, 29(5):594-596. doi:10.1016/j.healun.2009.12.001
• [28]Kotsch K, Ulrich F, Reutzel-Selke A, Pascher A, Faber W, Warnick P, Hoffman S, Francuski M, Kunert C, Kuecuek O, Schumacher G, Wesslau C, Lun A, Kohler S, Weiss S, Tullius S. G, Neuhaus P, Pratschke J: Methylprednisolone therapy in deceased donors reduces inflammation in the donor liver and improves outcome after liver transplantation: a prospective randomized controlled trial. Ann Surg 2008, 248(6):1042-1050. doi:10.1097/SLA.0b013e318190e70c
• [29]Venkateswaran RV, Patchell VB, Wilson IC, Mascaro JG, Thompson RD, Quinn DW, Stockley RA, Coote JH, Bonser RS: Early donor management increases the retrieval rate of lungs for transplantation. Ann Thorac Surg 2008, 85(1):278-86286. doi:10.1016/j.athoracsur.2007.07.092
• [30]James SR, Ranasinghe AM, Venkateswaran R, McCabe CJ, Franklyn JA, Bonser RS: The effects of acute triiodothyronine therapy on myocardial gene expression in brain stem dead cardiac donors. J Clin Endocrinol Metab 2010, 95(3):1338-1343. doi:10.1210/jc.2009-1659
• [31]Macdonald PS, Aneman A, Bhonagiri D, Jones D, O’callaghan G, Silvester W, Watson A, Dobb G: A systematic review and meta-analysis of clinical trials of thyroid hormone administration to brain dead potential organ donors*. Crit Care Med 2012, 40(5):1635-1644. doi:10.1097/CCM.0b013e3182416ee7
• [32]Hodel A: Effects of glucocorticoids on adrenal chromaffin cells. J Neuroendocrinology 2001, 13(2):216-220.
• [33]Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med 2005, 353(16):1711-1723. doi:10.1056/NEJMra050541
• [34]Lenth RV: Java Applets for Power and Sample Size [Computer Software]. http://homepage.stat.uiowa.edu/~rlenth/Power/ webcite
• [35]Nicolas-Robin A, Barouk JD, Amour J, Coriat P, Riou B, Langeron O: Hydrocortisone supplementation enhances hemodynamic stability in brain-dead patients. Anesthesiology 2010, 112(5):1204-1210. doi:10.1097/ALN.0b013e3181d4f34d
• [36]Rech TH, Moraes RB, Crispim D, Czepielewski MA, Leitão CB: Management of the brain-dead organ donor. Transplantation 2013, 95(7):966-974. doi:10.1097/TP.0b013e318283298e
• [37]Dhar R, Cotton C, Coleman J, Brockmeier D, Kappel D, Marklin G, Wright R: Comparison of high- and low-dose corticosteroid regimens for organ donor management. J Crit Care 2013, 28(1):111-17. doi:10.1016/j.jcrc.2012.04.015
• [38]Amatschek S, Wilflingseder J, Pones M, Kainz A, Bodingbauer M, Mühlbacher F, Langer RM, Gerlei Z, Oberbauer R: The effect of steroid pretreatment of deceased organ donors on liver allograft function: A blinded randomized placebo-controlled trial. J Hepatol 2012, 56(6):1305-1309. doi:10.1016/j.jhep.2012.01.020
• [39]Bugge JF: Brain death and its implications for management of the potential organ donor. Acta Anaesthesiol Scand 2009, 53(10):1239-1250. doi:10.1111/j.1399-6576.2009.02064.x
• [40]Watson JD, Varley JG, Tomlin SJ, Medbak S, Perry L, Bouloux PM, Rees LH, Besser GM, Hinds CJ: Neuroendocrine and cardiovascular responses to high-dose corticosteroid therapy in canine endotoxin shock. Res Exp Med. Zeitschrift für die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie 1988, 188(5):329-339.
• [41]Dahmane D, Audard V, Hiesse C, Pessione F, Bentaarit B, Barrou B, Rondeau E, Cohen S, Lang P, Grimbert P: Retrospective follow-up of transplantation of kidneys from ‘marginal’ donors. Kidney Int 2006, 69(3):546-552. doi:10.1038/sj.ki.5000102
• [42]Ahsan N, Dhillon S, Holman M, Yang HC: Adverse effect of donor vasopressor support on immediate and one-year kidney allograft function. Surgery 1996, 120(4):663-666.
• [43]Bouma HR, Ploeg RJ, Schuurs TA: Signal transduction pathways involved in brain death-induced renal injury. Am J Transplant: Official J Am Soc Transplant Am Soc Transplant Surg 2009, 9(5):989-997. doi:10.1111/j.1600-6143.2009.02587.x
• [44]Atkinson C, Varela JC, Tomlinson S: Complement-dependent inflammation and injury in a murine model of brain dead donor hearts. Circ Res 2009, 105(11):1094-1101. doi:10.1161/CIRCRESAHA.109.194977
• [45]Damman J, Nijboer WN, Schuurs TA, Leuvenink HG, Morariu AM, Tullius SG, van Goor H, Ploeg RJ, Seelen MA: Local renal complement C3 induction by donor brain death is associated with reduced renal allograft function after transplantation. Nephrol Dial Transplant 2011, 26(7):2345-2354. doi:10.1093/ndt/gfq717
• [46]Terry CM, Clikeman JA, Hoidal JR, Callahan KS: TNF-α and IL-1α induce heme oxygenase-1 via protein kinase C, Ca2+, and phospholipase A2 in endothelial cells. Am J Physiol Heart Circ Physiol 1999, 276(5):1493-1501.
• [47]Hoeger S, Bergstraesser C, Selhorst J, Fontana J, Birck R, Waldherr R, Beck G, Sticht C, Seelen MA, van Son WJ, Leuvenink H, Ploeg R, Schnuelle P, Yard BA: Modulation of brain dead induced inflammation by vagus nerve stimulation. Am J Transplant: Official J Am Soc Transplant Am Soc Transplant Surg 2010, 10(3):477-489. doi:10.1111/j.1600-6143.2009.02951.x
• [48]Stott B, Korbelik M: Activation of complement C3, C5, and C9 genes in tumors treated by photodynamic therapy. Cancer Immunol Immunotherapy 2006, 56(5):649-658. doi:10.1007/s00262-006-0221-z