**i.** Accomodation

**5. Complexities in the diagnosis of antibody mediated rejection (Table 3)**

The diagnosis of AMR has improved dramatically with the advent of C4d staining and the ability to detect DSA [41]. The diagnosis of acute AMR according to BANFF criteria requires a triad of [1] histological evidence of graft damage including acute-tubular necrosis-like minimal inflammation, capillaritis and/or glomerulitis and/or thromboses and arteritis, [2] immunological evidence of complement activation inferred by C4d positivity in the peritub‐ ular capillaries (PTC), and [3] presence of DSA; whereas the diagnostic criteria for chronic AMR requires [1] morphological evidence of chronic damage of the allograft including duplication of glomerular basement membrane, lamination of peritubular capillaries, arterial intimal fibrosis or interstitial fibrosis/tubular atrophy, [2] diffuse C4d deposition in PTC, and [3] presence of DSA [42]. C4d, a complement split product, is formed by the binding and activation of the classical complement pathway by DSA, which then binds covalently to specific target molecules on the endothelium of PTC and is therefore considered a footprint of AMR [43]. The sensitivity and specificity of diffuse PTC C4d staining for the presence of DSA

> Chronic antibody-mediated rejection Peritubular capillary C4d deposition Circulating anti-HLA donor specific antibody Morphological evidence of chronic tissue injury (e.g. transplant glomerulopathy, interstitial fibrosis, tubular

Correlates with AMR and graft survival

Useful to detect AMR, diffuse > focal, PTC C4d negative in

No association with graft survival or Similar sensitivity and specificity but detecting AMR compared with C4d

atrophy)

60% AMR

deposition

is >95% [44].

Acute antibody-mediated rejection Peritubular capillary C4d deposition Circulating anti-HLA donor specific antibody Morphological evidence of acute tissue injury (e.g.

114 Current Issues and Future Direction in Kidney Transplantation

capillaritis, glomerulitis)

AMR

capillary

Controversies of C4d staining Peritubular capillary C4d deposition Glomerular C4d deposition Arteriolar C4d deposition

Problems with C4d staining:

Erythrocyte C4d deposition better PPV in peritubular

Abbreviation: AMR – antibody mediated rejection, HLA – human leukocyte antigen

clinical significance of these deposits remain debatable.

**Table 3.** Histological criteria for acute and chronic antibody mediated rejection and corresponding table of controversies of relying on peritubular capillary C4d deposition as a marker for antibody mediated rejection.

However, there are concerns regarding whether the presence of C4d within peritubular capillaries is essential for the diagnosis of AMR with reports of C4d-negative AMR being identified. There have been a few studies that have demonstrated an association between glomerular or erythrocyte C4d deposition and the presence of acute and chronic AMR but the The presence of C4d deposition in PTC does not always denote the presence of AMR or tissue injury. In ABO-incompatible renal transplant, the presence of PTC C4d staining often occurs in the absence of tissue injury or AMR, a process known as accommodation and may be observed in >70% of ABO-incompatible transplants; whereas the presence of PTC C4d staining in HLA-incompatible grafts correlates strongly with the presence of AMR [45].
