*3.2. Complement-Related Biomarkers*

Complement system is deeply involved in ABMR and can therefore provide potential biomarkers related to this process.

The C4d deposition has been considered the gold standard for ABMR diagnosis for several years, indicating activation of Classical pathway of Complement; however, all Complement pathways have been proved to be involved in ABMR, leading to recruitment and activation of leukocytes such as Natural Killer cells, monocytes/macrophages, and lymphocytes [97].

Bobka S. et al. also demonstrated an increased Complement activation in pre-transplant biopsies from diabetic, hypertensive, or smoking donors, suggesting a predictive value of Complement activation in donor biopsies for later outcome [98]. Expression of these Complement components at time of diagnosis of ABMR was associated with higher serum creatinine and more severe morphological changes. As further evidence, C5 blockade prevented ABMR and stabilized long-term renal function.

In addition, EVs shed by endothelial cell expressing C4d (CD144<sup>+</sup> C4d+) are increased in ABMR and correlate with its severity and response to treatment [99] and plasma levels of complement activation fragments C4a and Ba are increased in ABMR [60]. Single nucleotide polymorphisms (SNP) of complement C3 gene have also been found to correlate with ABMR [100]. Upregulation of intrarenal complement regulatory genes and complement transcripts in peripheral blood of ABO-incompatible KTx has already been discussed in "Transcriptomic Studies" [92]. Altogether, these data support the use of Complement Factors as potential biomarkers in ABMR.
