The complement system is divided into 3 major pathways the classical, lectin, and alternative pathways, the end result of these pathways is cleavage of C3 into C3a and C3b, C3b activate cleavage of C5 to C5 a, and C5b.

1- C5b initiate formation of membrane attack complex (MAC) with subsequent lysis of target cell

2- C3b is deposited on target cells (opsonization) then phagocytosis by cells that have complement receptor

3- C3 a, C5a are potent anaphylatoxin that initiate inflammation, vasodilatation

⦁ In the classical pathway, the initiating step is formation of Ag-Ab complexes.(1)

⦁ In the lectin pathway the initiating step is binding of lectins to sugar on the surface of microorganism. (2)

⦁ In alternative pathway (AP) no antigen exposure and no antibody needed for activation of this system, it acts independently (3)

Complement system has important rule in graft dysfunction which is very evident in the following two situations :

1- Antibody mediatied rejection

ABMR is the most common cause of graft failure 

Active ABMR occurs due to binding of circulating antibodies to donor alloantigens located on graft endothelium (HLA class I, HLA class II, ABO – antigens or non HLA antigens on endothelial cells) 

Ag-Ab complexes activate classical complement pathway with final production of c5b, c3b, c3a, c5a leading to inflammation, cell damage and graft dysfunction

One of degradation products of classical pathway is C4b which is converted to C4d, the later binds covalently to endothelium of peritubular capillaries (PTCS) and acts as a foot print for complement activation and ABMR.

C4d normally can be detected in mesangium, but deposition in PTCS occurs only in ABMR, deposition of C4d may be defuse if > 50% of PTCS are involved or may be focal if < 50 % of PTCS are involved (4)

Diagnosis of ABMR:

⦁ Histologic evidence of acute tissue injury (capillaritis and/or glomerulitis)

⦁ Evidence of antibody interaction with vascular endothelium (C4d staining in peritubular capillaries [PTCs])

⦁ Serologic evidence of circulating DSAs 

If the patient has first criteria and only one of the other 2 criteria, the patient is considered to have ABMR, this means C4d staining can replace DSA, and C4d negative ABMR exists (ABMR without activation of complement cascade) (5)

Patients with DSA who are C4d positive has lower graft survival than those who are C4d negative, this means that it is a marker for severity and has prognostic implication (6). but C4d negative patients have higher rate of developing transplant glomerulopathy if untreated

In one study it was found that C4d positive staining was present in all patients with ABMR and no patients with TCMR (7), moreover it was found that C4d was 95 % sensitive and 96 % specific for the presence of DSA

in ABO -incompatible kidney transplants some times C4d staining occur in the absence of histologic features of injury this is called graft accommodation [8].

Current treatment is directed against depleting B cells (rituximab and ATG added if mixed ABMR+ TCMR) , decreasing production of antibodies (IVIG) and removing DSA (plasmapheresis- used in early ABMR < 1 y) and decreasing inflamation produced by rejection (high dose corticosteroids) this is in combination with intensification of maintenance immunosuppression, antiviral and antimicrobial prophylaxis

Eculizumab is a monoclonal antibody, fully humanized, directed against C5 so inhibit the formation of MAC, it is FDA approved in the treatment of PNH and aHUS

In renal transplantation there is no of randomized controlled studies that prove the efficacy and safety in the treatment of ABMR, some reports its efficacy for treatment of acute refractory C4d positive (9), on the other hand, ABMR occur in patient already receiving eculizumab for other indication such as a HUS

2- Complement medicated TMA 

Complement medicated TMA occur due to abnormal regulation of alternative pathway of complement due to mutation in either :
⦁ Regulators (factor H, I) in the form of loss of function or
⦁ Activators (C3, factor B) in the form of gaining of functions
leading to uncontrolled activation of complement system
 
TMA is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and AKI that if untreated can cause graft loss

Post transplantation TMA can occur either in the form of : 

1- Recurrent disease (nearly all patients have complement medicated TMA)

It is recommended that all patients with complement mediated TMA to use living- unrelated or deceased donor kidney and all patients with recurrent TMA to be considered as having complement mediated TMA and should be treated with eculizumab. 

Observational date suggest that in recurrent TMA post transplant eculizumab introduction leads to elevation of platelet count, decrease in LDH in most of patients and improve kidney function in 50% of patients (10)

2- Denovo TMA (due to immunosuppressive drugs, ABMR, viral infections)

All patients with denovo TMA should be evaluated for genetic mutations, and all possible reversible causes should be treated till having the result of genetic testing, if gentetic mutation found or if patient has progressive disease despite correcting suspected etiology, eculizumab should be started.

REFERANCES
1- Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol 2014; 5:520.
2- Kjaer TR, Thiel S, Andersen GR. Toward a structure-based comprehension of the lectin pathway of complement. Mol Immunol 2013; 56:222.
3- Thurman JM, Holers VM. The central role of the alternative complement pathway in human disease. J Immunol 2006; 176:1305.
4- Feucht HE, Felber E, Gokel MJ, et al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 1991; 86:464.
5- Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018; 18:293.
6- Böhmig GA, Exner M, Habicht A, et al. Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. J Am Soc Nephrol 2002; 13:1091.
7- Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10:2208.
8- Bach FH, Turman MA, Vercellotti GM, et al. Accommodation: a working paradigm for progressing toward clinical discordant xenografting. Transplant Proc 1991; 23:205.
9- Yamamoto T, Watarai Y, Futamura K, et al. Efficacy of Eculizumab Therapy for Atypical Hemolytic Uremic Syndrome Recurrence and Antibody-Mediated Rejection Progress After Renal Transplantation With Preformed Donor-Specific Antibodies: Case Report. Transplant Proc 2017; 49:159.
10-Legendre CM, Licht C, Muus P, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 2013; 368:2169.