**4. Clinical relevance of non-anti-HLA donor-specific antibodies (Table 2)**

Although it is well established that AMR is attributed to the presence of class I and/or II DSA, non-donor HLA-antibodies and other non-HLA antibodies have been implicated in the development of acute and chronic AMR following kidney transplantation. *Opelz G et al* and others have demonstrated that increasing panel reactive antibodies (PRA) in HLA-identical sibling transplants was associated with a greater risk of rejection (defined as functional graft survival) and poorer graft survival (PRA 0% 10-year graft survival 72%, PRA 1-50% 63%, PRA >50% 55%; o<0.01) suggesting that immune response against non-HLA targets may be important in kidney transplantation, especially in the prediction of chronic graft loss [38]. Alloantigenic and tissue-specific autoantigenic targets of non-HLA-DSA and non-HLA antibodies may include various minor histocompatibility antigens, major histocompatibility complex (MHC) class I chain-related gene A (MICA) antigens, endothelial cell, vimentin, collagen V, glutathione-S-transferase T1, agrin, and angiotensin II receptor type I. Table 2 provides an up-to-date summary of the significance of these non-HLA-DSA and non-HLA antibodies in kidney transplantation and discuss the interplay between alloimmunity and autoreactivity in renal allograft rejection [39, 40].

Detection of Antibody-Mediated Rejection in Kidney Transplantation and the Management of Highly Sensitised… http://dx.doi.org/10.5772/54735 113

suppression to better assess immune reactivity [25, 30-33]. Although there is no current con‐ sensus on the level of clinically significant DSA identified by flow cytometric or Luminex assays, most studies have demonstrated that increasing single, peak or total DSA levels were associated with an incremental risk of rejection and/or graft loss [29, 34]. Recent stud‐ ies have suggested that the detection of C1q-fixing DSA (i.e. the potential to identify DSA that can activate complements by binding C1q) may be more accurate in predicting acute rejection, biopsy C4d-deposition, transplant glomerulopathy and late graft failure following kidney transplantation and the authors suggested that the absence of C1q-positive de novo DSA has a high negative predictive value for transplant glomerulopathy (100%) and graft failure (88%) [35]. However, a recent retrospective study showed that the identification of strong complement-activating DSA (of IgG subclasses 1 and 3) pre-transplant was unlikely to improve AMR risk stratification compared to patients with a combination of both strong and weak/no complement-activating DSA (of IgG subclasses 2 and 4) [36]. The clinical im‐ portance of C1q-specific DSA in predicting graft outcome remains controversial and not routinely performed in many transplanting centres [35, 37]. With the greater understanding of HLA antigens and anti-HLA antibodies, innovative techniques have been established to allow transplantation across positive CDC and/or flow cross-match barriers by removing circulating DSA and/or B or plasma cells and the success and outcomes of these initiatives

**4. Clinical relevance of non-anti-HLA donor-specific antibodies (Table 2)**

Although it is well established that AMR is attributed to the presence of class I and/or II DSA, non-donor HLA-antibodies and other non-HLA antibodies have been implicated in the development of acute and chronic AMR following kidney transplantation. *Opelz G et al* and others have demonstrated that increasing panel reactive antibodies (PRA) in HLA-identical sibling transplants was associated with a greater risk of rejection (defined as functional graft survival) and poorer graft survival (PRA 0% 10-year graft survival 72%, PRA 1-50% 63%, PRA >50% 55%; o<0.01) suggesting that immune response against non-HLA targets may be important in kidney transplantation, especially in the prediction of chronic graft loss [38]. Alloantigenic and tissue-specific autoantigenic targets of non-HLA-DSA and non-HLA antibodies may include various minor histocompatibility antigens, major histocompatibility complex (MHC) class I chain-related gene A (MICA) antigens, endothelial cell, vimentin, collagen V, glutathione-S-transferase T1, agrin, and angiotensin II receptor type I. Table 2 provides an up-to-date summary of the significance of these non-HLA-DSA and non-HLA antibodies in kidney transplantation and discuss the interplay between alloimmunity and

will be discussed later in this chapter.

112 Current Issues and Future Direction in Kidney Transplantation

autoreactivity in renal allograft rejection [39, 40].


Abbreviations: MICA – major histocompatibility complex class I chain-related gene A, ACR – acute cellular rejection, AMR – antibody mediated rejection, GBM – glomerular basement membrane, ELISA – enzyme-linked immunosorbent assay, HLA – human leukocyte antigen

**Table 2.** Association between non-HLA-DSA and non-HLA antibodies and renal transplant outcomes.
