The complement system is considered to be an important part of innate immune system with a significant role in inflammation processes. The activation can occur through classical, alternative, or lectin pathway, resulting in the creation of anaphylatoxins C3a and C5a, possessing a vast spectrum of immune functions, and the assembly of terminal complement cascade, capable of direct cell lysis. The activation processes are tightly regulated; inappropriate activation of the complement cascade plays a significant role in many renal diseases including organ transplantation. Moreover, complement cascade is activated during ischemia/reperfusion injury processes and influences delayed graft function of kidney allografts. Interestingly, complement system has been found to play a role in both acute cellular and antibody-mediated rejections and thrombotic microangiopathy. Therefore, complement system may represent an interesting therapeutical target in kidney transplant pathologies.

Department of Nephrology Transplant Center Institute for Clinical and Experimental Medicine Prague Czechia

Transplant Laboratory Transplant Center Institute for Clinical and Experimental Medicine Prague Czechia

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Merle NS, Noe R, Halbwachs-Mecarelli L, Fremeaux-Bacchi V, Roumenina LT. Complement system part II: role in immunity. Front Immunol (2015) 6:257.10.3389/fimmu.2015.00257 PubMed DOI PMC

Dunkelberger JR, Song WC. Complement and its role in innate and adaptive immune responses. Cell Res (2010) 20(1):34–50.10.1038/cr.2009.139 PubMed DOI

Bohlson SS, O’Conner SD, Hulsebus HJ, Ho MM, Fraser DA. Complement, c1q, and c1q-related molecules regulate macrophage polarization. Front Immunol (2014) 5:402.10.3389/fimmu.2014.00402 PubMed DOI PMC

Bubeck D. The making of a macromolecular machine: assembly of the membrane attack complex. Biochemistry (2014) 53(12):1908–15.10.1021/bi500157z PubMed DOI

Ogden CA, deCathelineau A, Hoffmann PR, Bratton D, Ghebrehiwet B, Fadok VA, et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J Exp Med (2001) 194(6):781–95.10.1084/jem.194.6.781 PubMed DOI PMC

Trouw LA, Bengtsson AA, Gelderman KA, Dahlbäck B, Sturfelt G, Blom AM. C4b-binding protein and factor H compensate for the loss of membrane-bound complement inhibitors to protect apoptotic cells against excessive complement attack. J Biol Chem (2007) 282(39):28540–8.10.1074/jbc.M704354200 PubMed DOI

Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J. The role of the anaphylatoxins in health and disease. Mol Immunol (2009) 46(14):2753–66.10.1016/j.molimm.2009.04.027 PubMed DOI PMC

Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement system part I – molecular mechanisms of activation and regulation. Front Immunol (2015) 6:262.10.3389/fimmu.2015.00262 PubMed DOI PMC

Molina H, Holers VM, Li B, Fung Y, Mariathasan S, Goellner J, et al. Markedly impaired humoral immune response in mice deficient in complement receptors 1 and 2. Proc Natl Acad Sci U S A (1996) 93(8):3357–61.10.1073/pnas.93.8.3357 PubMed DOI PMC

Strainic MG, Liu J, Huang D, An F, Lalli PN, Mugim N, et al. Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity (2008) 28(3):425–35.10.1016/j.immuni.2008.02.001 PubMed DOI PMC

Strainic MG, Shevach EM, An F, Lin F, Medof ME. Absence of signaling into CD4? cells via C3aR and C5aR enables autoinductive TGF-β1 signaling and induction of Foxp3? regulatory T cells. Nat Immunol (2013) 14(2):162–71.10.1038/ni.2499 PubMed DOI PMC

Sarma JV, Ward PA. The complement system. Cell Tissue Res (2011) 343(1):227–35.10.1007/s00441-010-1034-0 PubMed DOI PMC

Kishore U, Ghai R, Greenhough TJ, Shrive AK, Bonifati DM, Gadjeva MG, et al. Structural and functional anatomy of the globular domain of complement protein C1q. Immunol Lett (2004) 95(2):113–28.10.1016/j.imlet.2004.06.015 PubMed DOI PMC

Nauta AJ, Raaschou-Jensen N, Roos A, Daha MR, Madsen HO, Borrias-Essers MC, et al. Mannose-binding lectin engagement with late apoptotic and necrotic cells. Eur J Immunol (2003) 33(10):2853–63.10.1002/eji.200323888 PubMed DOI

Girija UV, Gingras AR, Marshall JE, Panchal R, Sheikh MA, Gál P, et al. Structural basis of the C1q/C1s interaction and its central role in assembly of the C1 complex of complement activation. Proc Natl Acad Sci U S A (2013) 110(34):13916–20.10.1073/pnas.1311113110 PubMed DOI PMC

Pangburn MK, Schreiber RD, Müller-Eberhard HJ. Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3. J Exp Med (1981) 154(3):856–67.10.1084/jem.154.3.856 PubMed DOI PMC

Li K, Gor J, Perkins SJ. Self-association and domain rearrangements between complement C3 and C3u provide insight into the activation mechanism of C3. Biochem J (2010) 431(1):63–72.10.1042/BJ20100759 PubMed DOI

Fearon DT, Austen KF. Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase. J Exp Med (1975) 142(4):856–63.10.1084/jem.142.4.856 PubMed DOI PMC

Kemper C, Atkinson JP, Hourcade DE. Properdin: emerging roles of a pattern-recognition molecule. Annu Rev Immunol (2010) 28:131–55.10.1146/annurev-immunol-030409-101250 PubMed DOI

Lesher AM, Nilsson B, Song WC. Properdin in complement activation and tissue injury. Mol Immunol (2013) 56(3):191–8.10.1016/j.molimm.2013.06.002 PubMed DOI PMC

Podack ER. Molecular composition of the tubular structure of the membrane attack complex of complement. J Biol Chem (1984) 259(13):8641–7. PubMed

Serna M, Giles JL, Morgan BP, Bubeck D. Structural basis of complement membrane attack complex formation. Nat Commun (2016) 7:10587.10.1038/ncomms10587 PubMed DOI PMC

Vogt W, Zimmermann B, Hesse D, Nolte R. Activation of the fifth component of human complement, C5, without cleavage, by methionine oxidizing agents. Mol Immunol (1992) 29(2):251–6.10.1016/0161-5890(92)90106-8 PubMed DOI

Distelmaier K, Adlbrecht C, Jakowitsch J, Winkler S, Dunkler D, Gerner C, et al. Local complement activation triggers neutrophil recruitment to the site of thrombus formation in acute myocardial infarction. Thromb Haemost (2009) 102(3):564–72.10.1160/TH09-02-0103 PubMed DOI

Howes JM, Richardson VR, Smith KA, Schroeder V, Somani R, Shore A, et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res (2012) 9(3):216–25.10.1177/1479164111432788 PubMed DOI

Huber-Lang M, Younkin EM, Sarma JV, Riedemann N, McGuire SR, Lu KT, et al. Generation of C5a by phagocytic cells. Am J Pathol (2002) 161(5):1849–59.10.1016/S0002-9440(10)64461-6 PubMed DOI PMC

Auger JL, Haasken S, Binstadt BA. Autoantibody-mediated arthritis in the absence of C3 and activating Fcγ receptors: C5 is activated by the coagulation cascade. Arthritis Res Ther (2012) 14(6):R269.10.1186/ar4117 PubMed DOI PMC

Foley JH, Walton BL, Aleman MM, O’Byrne AM, Lei V, Harrasser M, et al. Complement activation in arterial and venous thrombosis is mediated by plasmin. EBioMedicine (2016) 5:175–82.10.1016/j.ebiom.2016.02.011 PubMed DOI PMC

Ehrengruber MU, Geiser T, Deranleau DA. Activation of human neutrophils by C3a and C5A. Comparison of the effects on shape changes, chemotaxis, secretion, and respiratory burst. FEBS Lett (1994) 346(2–3):181–4.10.1016/0014-5793(94)00463-3 PubMed DOI

Hartmann K, Henz BM, Krüger-Krasagakes S, Köhl J, Burger R, Guhl S, et al. C3a and C5a stimulate chemotaxis of human mast cells. Blood (1997) 89(8):2863–70. PubMed

Nataf S, Davoust N, Ames RS, Barnum SR. Human T cells express the C5a receptor and are chemoattracted to C5a. J Immunol (1999) 162(7):4018–23. PubMed

Elsner J, Oppermann M, Czech W, Dobos G, Schöpf E, Norgauer J, et al. C3a activates reactive oxygen radical species production and intracellular calcium transients in human eosinophils. Eur J Immunol (1994) 24(3):518–22.10.1002/eji.1830240304 PubMed DOI

Elsner J, Oppermann M, Czech W, Kapp A. C3a activates the respiratory burst in human polymorphonuclear neutrophilic leukocytes via pertussis toxin-sensitive G-proteins. Blood (1994) 83(11):3324–31. PubMed

el-Lati SG, Dahinden CA, Church MK. Complement peptides C3a- and C5a-induced mediator release from dissociated human skin mast cells. J Invest Dermatol (1994) 102(5):803–6.10.1111/1523-1747.ep12378589 PubMed DOI

Fischer WH, Jagels MA, Hugli TE. Regulation of IL-6 synthesis in human peripheral blood mononuclear cells by C3a and C3a(desArg). J Immunol (1999) 162(1):453–9. PubMed

Strey CW, Markiewski M, Mastellos D, Tudoran R, Spruce LA, Greenbaum LE, et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J Exp Med (2003) 198(6):913–23.10.1084/jem.20030374 PubMed DOI PMC

Silasi-Mansat R, Zhu H, Georgescu C, Popescu N, Keshari RS, Peer G, et al. Complement inhibition decreases early fibrogenic events in the lung of septic baboons. J Cell Mol Med (2015) 19(11):2549–63.10.1111/jcmm.12667 PubMed DOI PMC

Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell (2002) 10(2):417–26.10.1016/S1097-2765(02)00599-3 PubMed DOI

Schroder K, Tschopp J. The inflammasomes. Cell (2010) 140(6):821–32.10.1016/j.cell.2010.01.040 PubMed DOI

Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks SS, Köhl J, et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood (2013) 122(20):3473–81.10.1182/blood-2013-05-502229 PubMed DOI

An LL, Mehta P, Xu L, Turman S, Reimer T, Naiman B, et al. Complement C5a potentiates uric acid crystal-induced IL-1β production. Eur J Immunol (2014) 44(12):3669–79.10.1002/eji.201444560 PubMed DOI

Samstad EO, Niyonzima N, Nymo S, Aune MH, Ryan L, Bakke SS, et al. Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release. J Immunol (2014) 192(6):2837–45.10.4049/jimmunol.1302484 PubMed DOI PMC

Suresh R, Chandrasekaran P, Sutterwala FS, Mosser DM. Complement-mediated ’bystander’ damage initiates host NLRP3 inflammasome activation. J Cell Sci (2016) 129(9):1928–39.10.1242/jcs.179291 PubMed DOI PMC

Fujita T, Inoue T, Ogawa K, Iida K, Tamura N. The mechanism of action of decay-accelerating factor (DAF). DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb. J Exp Med (1987) 166(5):1221–8.10.1084/jem.166.5.1221 PubMed DOI PMC

Krych-Goldberg M, Hauhart RE, Subramanian VB, Yurcisin BM, II, Crimmins DL, Hourcade DE, et al. Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5 convertases. J Biol Chem (1999) 274(44):31160–8.10.1074/jbc.274.44.31160 PubMed DOI

Hourcade DE, Mitchell L, Kuttner-Kondo LA, Atkinson JP, Medof ME. Decay-accelerating factor (DAF), complement receptor 1 (CR1), and factor H dissociate the complement AP C3 convertase (C3bBb) via sites on the type A domain of Bb. J Biol Chem (2002) 277(2):1107–12.10.1074/jbc.M109322200 PubMed DOI

Java A, Liszewski MK, Hourcade DE, Zhang F, Atkinson JP. Role of complement receptor 1 (CR1; CD35) on epithelial cells: a model for understanding complement-mediated damage in the kidney. Mol Immunol (2015) 67(2 Pt B):584–95.10.1016/j.molimm.2015.07.016 PubMed DOI PMC

Blom AM. Structural and functional studies of complement inhibitor C4b-binding protein. Biochem Soc Trans (2002) 30(Pt 6):978–82.10.1042/bst0300978 PubMed DOI

Perkins SJ, Nan R, Li K, Khan S, Miller A. Complement factor H-ligand interactions: self-association, multivalency and dissociation constants. Immunobiology (2012) 217(2):281–97.10.1016/j.imbio.2011.10.003 PubMed DOI

Seya T, Turner JR, Atkinson JP. Purification and characterization of a membrane protein (gp45-70) that is a cofactor for cleavage of C3b and C4b. J Exp Med (1986) 163(4):837–55.10.1084/jem.163.4.837 PubMed DOI PMC

Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant (2011) 11(11):2279–96.10.1111/j.1600-6143.2011.03754.x PubMed DOI PMC

Arumugam TV, Shiels IA, Woodruff TM, Granger DN, Taylor SM. The role of the complement system in ischemia-reperfusion injury. Shock (2004) 21(5):401–9.10.1097/00024382-200405000-00002 PubMed DOI

Bohmova R, Viklicky O. Renal ischemia–reperfusion injury: an inescapable event affecting kidney transplantation outcome. Folia Microbiol (Praha) (2001) 46(4):267–76.10.1007/BF02815613 PubMed DOI

Wohlfahrtova M, Brabcova I, Zelezny F, Balaz P, Janousek L, Honsova E, et al. Tubular atrophy and low netrin-1 gene expression are associated with delayed kidney allograft function. Transplantation (2014) 97(2):176–83.10.1097/TP.0b013e3182a95d04 PubMed DOI

Serinsöz E, Bock O, Gwinner W, Schwarz A, Haller H, Kreipe H, et al. Local complement C3 expression is upregulated in humoral and cellular rejection of renal allografts. Am J Transplant (2005) 5(6):1490–4.10.1111/j.1600-6143.2005.00873.x PubMed DOI

Thurman JM, Royer PA, Ljubanovic D, Dursun B, Lenderink AM, Edelstein CL, et al. Treatment with an inhibitory monoclonal antibody to mouse factor B protects mice from induction of apoptosis and renal ischemia/reperfusion injury. J Am Soc Nephrol (2006) 17(3):707–15.10.1681/ASN.2005070698 PubMed DOI

Farrar CA, Zhou W, Lin T, Sacks SH. Local extravascular pool of C3 is a determinant of postischemic acute renal failure. FASEB J (2006) 20(2):217–26.10.1096/fj.05-4747com PubMed DOI

De Vries B, Matthijsen RA, Wolfs TG, Van Bijnen AA, Heeringa P, Buurman WA. Inhibition of complement factor C5 protects against renal ischemia-reperfusion injury: inhibition of late apoptosis and inflammation. Transplantation (2003) 75(3):375–82.10.1097/01.TP.0000044455.05584.2A PubMed DOI

de Vries B, Köhl J, Leclercq WK, Wolfs TG, van Bijnen AA, Heeringa P, et al. Complement factor C5a mediates renal ischemia-reperfusion injury independent from neutrophils. J Immunol (2003) 170(7):3883–9.10.4049/jimmunol.170.7.3883 PubMed DOI

Lewis AG, Köhl G, Ma Q, Devarajan P, Köhl J. Pharmacological targeting of C5a receptors during organ preservation improves kidney graft survival. Clin Exp Immunol (2008) 153(1):117–26.10.1111/j.1365-2249.2008.03678.x PubMed DOI PMC

Peng Q, Li K, Smyth LA, Xing G, Wang N, Meader L, et al. C3a and C5a promote renal ischemia-reperfusion injury. J Am Soc Nephrol (2012) 23(9):1474–85.10.1681/ASN.2011111072 PubMed DOI PMC

Lalli PN, Strainic MG, Lin F, Medof ME, Heeger PS. Decay accelerating factor can control T cell differentiation into IFN-gamma-producing effector cells via regulating local C5a-induced IL-12 production. J Immunol (2007) 179(9):5793–802.10.4049/jimmunol.179.9.5793 PubMed DOI PMC

van Werkhoven MB, Damman J, van Dijk MC, Daha MR, de Jong IJ, Leliveld A, et al. Complement mediated renal inflammation induced by donor brain death: role of renal C5a-C5aR interaction. Am J Transplant (2013) 13(4):875–82.10.1111/ajt.12130 PubMed DOI

Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh HC, et al. Expression of complement components differs between kidney allografts from living and deceased donors. J Am Soc Nephrol (2009) 20(8):1839–51.10.1681/ASN.2008111145 PubMed DOI PMC

Kusaka M, Pratschke J, Wilhelm MJ, Ziai F, Zandi-Nejad K, Mackenzie HS, et al. Activation of inflammatory mediators in rat renal isografts by donor brain death. Transplantation (2000) 69(3):405–10.10.1097/00007890-200002150-00017 PubMed DOI

Damman J, Nijboer WN, Schuurs TA, Leuvenink HG, Morariu AM, Tullius SG, et al. Local renal complement C3 induction by donor brain death is associated with reduced renal allograft function after transplantation. Nephrol Dial Transplant (2011) 26(7):2345–54.10.1093/ndt/gfq717 PubMed DOI

Atkinson C, Floerchinger B, Qiao F, Casey S, Williamson T, Moseley E, et al. Donor brain death exacerbates complement-dependent ischemia/reperfusion injury in transplanted hearts. Circulation (2013) 127(12):1290–9.10.1161/CIRCULATIONAHA.112.000784 PubMed DOI PMC

Damman J, Seelen MA, Moers C, Daha MR, Rahmel A, Leuvenink HG, et al. Systemic complement activation in deceased donors is associated with acute rejection after renal transplantation in the recipient. Transplantation (2011) 92(2):163–9.10.1097/TP.0b013e318222c9a0 PubMed DOI

Fuquay R, Renner B, Kulik L, McCullough JW, Amura C, Strassheim D, et al. Renal ischemia-reperfusion injury amplifies the humoral immune response. J Am Soc Nephrol (2013) 24(7):1063–72.10.1681/ASN.2012060560 PubMed DOI PMC

Raedler H, Vieyra MB, Leisman S, Lakhani P, Kwan W, Yang M, et al. Anti-complement component C5 mAb synergizes with CTLA4Ig to inhibit alloreactive T cells and prolong cardiac allograft survival in mice. Am J Transplant (2011) 11(7):1397–406.10.1111/j.1600-6143.2011.03561.x PubMed DOI PMC

Williams JP, Pechet TT, Weiser MR, Reid R, Kobzik L, Moore FD, Jr, et al. Intestinal reperfusion injury is mediated by IgM and complement. J Appl Physiol (1999) 86(3):938–42. PubMed

Zhang M, Austen WG, Jr, Chiu I, Alicot EM, Hung R, Ma M, et al. Identification of a specific self-reactive IgM antibody that initiates intestinal ischemia/reperfusion injury. Proc Natl Acad Sci U S A (2004) 101(11):3886–91.10.1073/pnas.0400347101 PubMed DOI PMC

Zhang M, Takahashi K, Alicot EM, Vorup-Jensen T, Kessler B, Thiel S, et al. Activation of the lectin pathway by natural IgM in a model of ischemia/reperfusion injury. J Immunol (2006) 177(7):4727–34.10.4049/jimmunol.177.7.4727 PubMed DOI

Busche MN, Pavlov V, Takahashi K, Stahl GL. Myocardial ischemia and reperfusion injury is dependent on both IgM and mannose-binding lectin. Am J Physiol Heart Circ Physiol (2009) 297(5):H1853–9.10.1152/ajpheart.00049.2009 PubMed DOI PMC

Diepenhorst GM, van Gulik TM, Hack CE. Complement-mediated ischemia-reperfusion injury: lessons learned from animal and clinical studies. Ann Surg (2009) 249(6):889–99.10.1097/SLA.0b013e3181a38f45 PubMed DOI

Zhou W, Farrar CA, Abe K, Pratt JR, Marsh JE, Wang Y, et al. Predominant role for C5b-9 in renal ischemia/reperfusion injury. J Clin Invest (2000) 105(10):1363–71.10.1172/JCI8621 PubMed DOI PMC

Hart ML, Ceonzo KA, Shaffer LA, Takahashi K, Rother RP, Reenstra WR, et al. Gastrointestinal ischemia-reperfusion injury is lectin complement pathway dependent without involving C1q. J Immunol (2005) 174(10):6373–80.10.4049/jimmunol.174.10.6373 PubMed DOI

Lee H, Green DJ, Lai L, Hou YJ, Jensenius JC, Liu D, et al. Early complement factors in the local tissue immunocomplex generated during intestinal ischemia/reperfusion injury. Mol Immunol (2010) 47(5):972–81.10.1016/j.molimm.2009.11.022 PubMed DOI PMC

Stahl GL, Xu Y, Hao L, Miller M, Buras JA, Fung M, et al. Role for the alternative complement pathway in ischemia/reperfusion injury. Am J Pathol (2003) 162(2):449–55.10.1016/S0002-9440(10)63839-4 PubMed DOI PMC

Miwa T, Sato S, Gullipalli D, Nangaku M, Song WC. Blocking properdin, the alternative pathway, and anaphylatoxin receptors ameliorates renal ischemia-reperfusion injury in decay-accelerating factor and CD59 double-knockout mice. J Immunol (2013) 190(7):3552–9.10.4049/jimmunol.1202275 PubMed DOI PMC

Collard CD, Väkevä A, Morrissey MA, Agah A, Rollins SA, Reenstra WR, et al. Complement activation after oxidative stress: role of the lectin complement pathway. Am J Pathol (2000) 156(5):1549–56.10.1016/S0002-9440(10)65026-2 PubMed DOI PMC

Collard CD, Montalto MC, Reenstra WR, Buras JA, Stahl GL. Endothelial oxidative stress activates the lectin complement pathway: role of cytokeratin 1. Am J Pathol (2001) 159(3):1045–54.10.1016/S0002-9440(10)61779-8 PubMed DOI PMC

de Vries B, Walter SJ, Peutz-Kootstra CJ, Wolfs TG, van Heurn LW, Buurman WA. The mannose-binding lectin-pathway is involved in complement activation in the course of renal ischemia-reperfusion injury. Am J Pathol (2004) 165(5):1677–88.10.1016/S0002-9440(10)63424-4 PubMed DOI PMC

Møller-Kristensen M, Wang W, Ruseva M, Thiel S, Nielsen S, Takahashi K, et al. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol (2005) 61(5):426–34.10.1111/j.1365-3083.2005.01591.x PubMed DOI

Asgari E, Farrar CA, Lynch N, Ali YM, Roscher S, Stover C, et al. Mannan-binding lectin-associated serine protease 2 is critical for the development of renal ischemia reperfusion injury and mediates tissue injury in the absence of complement C4. FASEB J (2014) 28(9):3996–4003.10.1096/fj.13-246306 PubMed DOI PMC

Yu ZX, Qi S, Lasaro MA, Bouchard K, Dow C, Moore K, et al. Targeting complement pathways during cold ischemia and reperfusion prevents delayed graft function. Am J Transplant (2016) 16(9):2589–97.10.1111/ajt.13797 PubMed DOI

Business Wire. Alexion Announces Top-Line Results from Phase 2/3 PROTECT Study of Eculizumab (Soliris®) for the Prevention of Delayed Graft Function (DGF) After Kidney Transplantation. (2017). Available from: http://www.businesswire.com/news/home/20161221005838/en/Alexion-Announces-Top-Line-Results-Phase-23-PROTECT

Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant (2010) 10(7):1517–23.10.1111/j.1600-6143.2010.03156.x PubMed DOI

Ardalan MR. Review of thrombotic microangiopathy (TMA), and post-renal transplant TMA. Saudi J Kidney Dis Transpl (2006) 17(2):235–44. PubMed

Benz K, Amann K. Thrombotic microangiopathy: new insights. Curr Opin Nephrol Hypertens (2010) 19(3):242–7.10.1097/MNH.0b013e3283378f25 PubMed DOI

Ponticelli C. De novo thrombotic microangiopathy. An underrated complication of renal transplantation. Clin Nephrol (2007) 67(6):335–40.10.5414/CNP67335 PubMed DOI

Broeders EN, Stordeur P, Rorive S, Dahan K. A ’silent’, new polymorphism of factor H and apparent de novo atypical haemolytic uraemic syndrome after kidney transplantation. BMJ Case Rep (2014).10.1136/bcr-2014-207630 PubMed DOI PMC

Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med (2013) 368(23):2169–81.10.1056/NEJMoa1208981 PubMed DOI

Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int (2015) 87(5):1061–73.10.1038/ki.2014.423 PubMed DOI PMC

Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, et al. Eculizumab for atypical hemolytic uremic syndrome recurrence in renal transplantation. Am J Transplant (2012) 12(12):3337–54.10.1111/j.1600-6143.2012.04252.x PubMed DOI

Passwell J, Schreiner GF, Non-aka M, Beuscher HU, Colten HR. Local extrahepatic expression of complement genes C3, factor B, C2, and C4 is increased in murine lupus nephritis. J Clin Invest (1988) 82(5):1676–84.10.1172/JCI113780 PubMed DOI PMC

Pratt JR, Basheer SA, Sacks SH. Local synthesis of complement component C3 regulates acute renal transplant rejection. Nat Med (2002) 8(6):582–7.10.1038/nm0602-582 PubMed DOI

Cravedi P, Leventhal J, Lakhani P, Ward SC, Donovan MJ, Heeger PS. Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant (2013) 13(10):2530–9.10.1111/ajt.12405 PubMed DOI PMC

van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS. Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol (2013) 190(12):5921–5.10.4049/jimmunol.1300847 PubMed DOI PMC

Gueler F, Rong S, Gwinner W, Mengel M, Bröcker V, Schön S, et al. Complement 5a receptor inhibition improves renal allograft survival. J Am Soc Nephrol (2008) 19(12):2302–12.10.1681/ASN.2007111267 PubMed DOI PMC

Li K, Anderson KJ, Peng Q, Noble A, Lu B, Kelly AP, et al. Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood (2008) 112(13):5084–94.10.1182/blood-2008-05-156646 PubMed DOI

Kwan WH, van der Touw W, Paz-Artal E, Li MO, Heeger PS. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med (2013) 210(2):257–68.10.1084/jem.20121525 PubMed DOI PMC

Zheng QY, Liang SJ, Li GQ, Lv YB, Li Y, Tang M, et al. Complement component 3 deficiency prolongs MHC-II disparate skin allograft survival by increasing the CD4(+) CD25(+) regulatory T cells population. Sci Rep (2016) 6:33489.10.1038/srep33489 PubMed DOI PMC

Cheng HB, Chen RY, Wu JP, Chen L, Liang YH, Pan HF, et al. Complement C4 induces regulatory T cells differentiation through dendritic cell in systemic lupus erythematosus. Cell Biosci (2015) 5:73.10.1186/s13578-015-0052-8 PubMed DOI PMC

Clarke EV, Weist BM, Walsh CM, Tenner AJ. Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation. J Leukoc Biol (2015) 97(1):147–60.10.1189/jlb.3A0614-278R PubMed DOI PMC

Liu J, Miwa T, Hilliard B, Chen Y, Lambris JD, Wells AD, et al. The complement inhibitory protein DAF (CD55) suppresses T cell immunity in vivo. J Exp Med (2005) 201(4):567–77.10.1084/jem.20040863 PubMed DOI PMC

Pavlov V, Raedler H, Yuan S, Leisman S, Kwan WH, Lalli PN, et al. Donor deficiency of decay-accelerating factor accelerates murine T cell-mediated cardiac allograft rejection. J Immunol (2008) 181(7):4580–9.10.4049/jimmunol.181.7.4580 PubMed DOI PMC

Kwan WH, Hashimoto D, Paz-Artal E, Ostrow K, Greter M, Raedler H, et al. Antigen-presenting cell-derived complement modulates graft-versus-host disease. J Clin Invest (2012) 122(6):2234–8.10.1172/JCI61019 PubMed DOI PMC

Yamanaka K, Kakuta Y, Miyagawa S, Nakazawa S, Kato T, Abe T, et al. Depression of complement regulatory factors in rat and human renal grafts is associated with the progress of acute T-cell mediated rejection. PLoS One (2016) 11(2):e0148881.10.1371/journal.pone.0148881 PubMed DOI PMC

Cardone J, Le Friec G, Vantourout P, Roberts A, Fuchs A, Jackson I, et al. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Nat Immunol (2010) 11(9):862–71.10.1038/ni.1917 PubMed DOI PMC

Parikova A, Fronek JP, Viklicky O. Living-donor kidney transplantation for atypical haemolytic uremic syndrome with pre-emptive eculizumab use. Transpl Int (2015) 28(3):366–9.10.1111/tri.12440 PubMed DOI

Farrar CA, Sacks SH. Mechanisms of rejection: role of complement. Curr Opin Organ Transplant (2014) 19(1):8–13.10.1097/MOT.0000000000000037 PubMed DOI

Berger SP, Roos A, Mallat MJ, Fujita T, de Fijter JW, Daha MR. Association between mannose-binding lectin levels and graft survival in kidney transplantation. Am J Transplant (2005) 5(6):1361–6.10.1111/j.1600-6143.2005.00841.x PubMed DOI

Imai N, Nishi S, Alchi B, Ueno M, Fukase S, Arakawa M, et al. Immunohistochemical evidence of activated lectin pathway in kidney allografts with peritubular capillary C4d deposition. Nephrol Dial Transplant (2006) 21(9):2589–95.10.1093/ndt/gfl210 PubMed DOI

Zwirner J, Felber E, Herzog V, Riethmüller G, Feucht HE. Classical pathway of complement activation in normal and diseased human glomeruli. Kidney Int (1989) 36(6):1069–77.10.1038/ki.1989.302 PubMed DOI

Feucht HE, Schneeberger H, Hillebrand G, Burkhardt K, Weiss M, Riethmüller G, et al. Capillary deposition of C4d complement fragment and early renal graft loss. Kidney Int (1993) 43(6):1333–8.10.1038/ki.1993.187 PubMed DOI

Lederer SR, Kluth-Pepper B, Schneeberger H, Albert E, Land W, Feucht HE. Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int (2001) 59(1):334–41.10.1046/j.1523-1755.2001.00495.x PubMed DOI

Herzenberg AM, Gill JS, Djurdjev O, Magil AB. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol (2002) 13(1):234–41. PubMed

Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant (2008) 8(4):753–60.10.1111/j.1600-6143.2008.02159.x PubMed DOI

Hass M. An updated Banff schema for diagnosis of antibody-mediated rejection in renal allografts. Curr Opin Organ Transplant (2014) 19(3):315–22.10.1097/MOT.0000000000000072 PubMed DOI

Miura M, Ogawa Y, Kubota KC, Harada H, Shimoda N, Ono T, et al. Donor-specific antibody in chronic rejection is associated with glomerulopathy, thickening of peritubular capillary basement membrane, but not C4d deposition. Clin Transplant (2007) 21:8–12.10.1111/j.1399-0012.2007.00710.x DOI

Sis B, Jhangri GS, Bunnag S, Allanach K, Kaplan B, Halloran PF. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant (2009) 9(10):2312–23.10.1111/j.1600-6143.2009.02761.x PubMed DOI

Sheen JH, Heeger PS. Effects of complement activation on allograft injury. Curr Opin Organ Transplant (2015) 20(4):468–75.10.1097/MOT.0000000000000216 PubMed DOI PMC

Fang Y, Xu C, Fu YX, Holers VM, Molina H. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. J Immunol (1998) 160(11):5273–9. PubMed

Dempsey PW, Allison ME, Akkaraju S, Goodnow CC, Fearon DT. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science (1996) 271(5247):348–50.10.1126/science.271.5247.348 PubMed DOI

Akiyoshi T, Hirohashi T, Alessandrini A, Chase CM, Farkash EA, Neal Smith R, et al. Role of complement and NK cells in antibody mediated rejection. Hum Immunol (2012) 73(12):1226–32.10.1016/j.humimm.2012.07.330 PubMed DOI PMC

Jane-Wit D, Manes TD, Yi T, Qin L, Clark P, Kirkiles-Smith NC, et al. Alloantibody and complement promote T cell-mediated cardiac allograft vasculopathy through non-canonical nuclear factor-κB signaling in endothelial cells. Circulation (2013) 128(23):2504–16.10.1161/CIRCULATIONAHA.113.002972 PubMed DOI PMC

Yabu JM, Higgins JP, Chen G, Sequeira F, Busque S, Tyan DB. C1q-fixing human leukocyte antigen antibodies are specific for predicting transplant glomerulopathy and late graft failure after kidney transplantation. Transplantation (2011) 91(3):342–7.10.1097/TP.0b013e318203fd26 PubMed DOI

Loupy A, Lefaucheur C, Vernerey D, Prugger C, Duong van Huyen JP, Mooney N, et al. Complement-binding anti-HLA antibodies and kidney-allograft survival. N Engl J Med (2013) 369(13):1215–26.10.1056/NEJMoa1302506 PubMed DOI

Crespo M, Torio A, Mas V, Redondo D, Pérez-Sáez MJ, Mir M, et al. Clinical relevance of pretransplant anti-HLA donor-specific antibodies: does C1q-fixation matter? Transpl Immunol (2013) 29(1–4):28–33.10.1016/j.trim.2013.07.002 PubMed DOI

Porcheray F, DeVito J, Helou Y, Dargon I, Fraser JW, Nobecourt P, et al. Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection. Am J Transplant (2012) 12(8):2088–97.10.1111/j.1600-6143.2012.04053.x PubMed DOI PMC

Porcheray F, DeVito J, Yeap BY, Xue L, Dargon I, Paine R, et al. Chronic humoral rejection of human kidney allografts associates with broad autoantibody responses. Transplantation (2010) 89(10):1239–46.10.1097/TP.0b013e3181d72091 PubMed DOI PMC

Porcheray F, Fraser JW, Gao B, McColl A, DeVito J, Dargon I, et al. Polyreactive antibodies developing amidst humoral rejection of human kidney grafts bind apoptotic cells and activate complement. Am J Transplant (2013) 13(10):2590–600.10.1111/ajt.12394 PubMed DOI PMC

Stegall MD, Diwan T, Raghavaiah S, Cornell LD, Burns J, Dean PG, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant (2011) 11(11):2405–13.10.1111/j.1600-6143.2011.03757.x PubMed DOI

Stegall MD, Chedid MF, Cornell LD. The role of complement in antibody-mediated rejection in kidney transplantation. Nat Rev Nephrol (2012) 8(11):670–8.10.1038/nrneph.2012.212 PubMed DOI

Alexion Pharmaceuticals Inc. Alexion Provides Update on Phase 2 Clinical Trial with Eculizumab in Antibody Mediated Rejection (AMR) in Living-Donor Kidney Transplant Recipients. (2017). Available from: http://news.alexionpharma.com/press-release/company-news/alexion-provides-update-phase-2-clinical-trial-eculizumab-antibody-mediat

Hirohashi T, Chase CM, Della Pelle P, Sebastian D, Alessandrini A, Madsen JC, et al. A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody. Am J Transplant (2012) 12(2):313–21.10.1111/j.1600-6143.2011.03836.x PubMed DOI PMC

Hidalgo LG, Sis B, Sellares J, Campbell PM, Mengel M, Einecke G, et al. NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant (2010) 10(8):1812–22.10.1111/j.1600-6143.2010.03201.x PubMed DOI

Hidalgo LG, Sellares J, Sis B, Mengel M, Chang J, Halloran PF. Interpreting NK cell transcripts versus T cell transcripts in renal transplant biopsies. Am J Transplant (2012) 12(5):1180–91.10.1111/j.1600-6143.2011.03970.x PubMed DOI

Kohei N, Tanaka T, Tanabe K, Masumori N, Dvorina N, Valujskikh A, et al. Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts. Kidney Int (2016) 89(6):1293–306.10.1016/j.kint.2016.02.030 PubMed DOI PMC

Legris T, Picard C, Todorova D, Lyonnet L, Laporte C, Dumoulin C, et al. Antibody-dependent NK cell activation is associated with late kidney allograft dysfunction and the complement-independent alloreactive potential of donor-specific antibodies. Front Immunol (2016) 7:288.10.3389/fimmu.2016.00288 PubMed DOI PMC

Davis AE, III, Mejia P, Lu F. Biological activities of C1 inhibitor. Mol Immunol (2008) 45(16):4057–63.10.1016/j.molimm.2008.06.028 PubMed DOI PMC

Paréj K, Dobó J, Závodszky P, Gál P. The control of the complement lectin pathway activation revisited: both C1-inhibitor and antithrombin are likely physiological inhibitors, while α2-macroglobulin is not. Mol Immunol (2013) 54(3–4):415–22.10.1016/j.molimm.2013.01.009 PubMed DOI

Tillou X, Poirier N, Le Bas-Bernardet S, Hervouet J, Minault D, Renaudin K, et al. Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in alloimmunized baboons. Kidney Int (2010) 78(2):152–9.10.1038/ki.2010.75 PubMed DOI

Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, et al. A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation (2015) 99(2):299–308.10.1097/TP.0000000000000592 PubMed DOI

Mauriello CT, Pallera HK, Sharp JA, Woltmann JL, Jr, Qian S, Hair PS, et al. A novel peptide inhibitor of classical and lectin complement activation including ABO incompatibility. Mol Immunol (2013) 53(1–2):132–9.10.1016/j.molimm.2012.07.012 PubMed DOI PMC

Sharp JA, Hair PS, Pallera HK, Kumar PS, Mauriello CT, Nyalwidhe JO, et al. Peptide inhibitor of complement C1 (PIC1) rapidly inhibits complement activation after intravascular injection in rats. PLoS One (2015) 10(7):e0132446.10.1371/journal.pone.0132446 PubMed DOI PMC

Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol (2007) 25(11):1256–64.10.1038/nbt1207-1488c PubMed DOI

Hillmen P, Young NS, Schubert J, Brodsky RA, Socié G, Muus P, et al. The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med (2006) 355(12):1233–43.10.1056/NEJMoa061648 PubMed DOI

Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, et al. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. Am J Kidney Dis (2016) 68(1):84–93.10.1053/j.ajkd.2015.12.034 PubMed DOI

Stewart ZA, Collins TE, Schlueter AJ, Raife TI, Holanda DG, Nair R, et al. Case report: eculizumab rescue of severe accelerated antibody-mediated rejection after ABO-incompatible kidney transplant. Transplant Proc (2012) 44(10):3033–6.10.1016/j.transproceed.2012.03.053 PubMed DOI

Chehade H, Rotman S, Matter M, Girardin E, Aubert V, Pascual M. Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient. Pediatrics (2015) 135(2):e551–5.10.1542/peds.2014-2275 PubMed DOI

Tran D, Boucher A, Collette S, Payette A, Royal V, Senécal L. Eculizumab for the treatment of severe antibody-mediated rejection: a case report and review of the literature. Case Rep Transplant (2016) 2016:9874261.10.1155/2016/9874261 PubMed DOI PMC

Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant (2015) 15(5):1293–302.10.1111/ajt.13168 PubMed DOI

Burbach M, Suberbielle C, Brochériou I, Ridel C, Mesnard L, Dahan K, et al. Report of the inefficacy of eculizumab in two cases of severe antibody-mediated rejection of renal grafts. Transplantation (2014) 98(10):1056–9.10.1097/TP.0000000000000184 PubMed DOI

Bentall A, Tyan DB, Sequeira F, Everly MJ, Gandhi MJ, Cornell LD, et al. Antibody-mediated rejection despite inhibition of terminal complement. Transpl Int (2014) 27(12):1235–43.10.1111/tri.12396 PubMed DOI

Rejection-associated Phenotype of De Novo Thrombotic Microangiopathy Represents a Risk for Premature Graft Loss

Intrarenal Complement System Transcripts in Chronic Antibody-Mediated Rejection and Recurrent IgA Nephropathy in Kidney Transplantation