**4.2. C4d-negative disease**

In 1991, Feucht and co-workers discovered peritubular capillary deposition of C4d, an inactive product of the classic complement pathway [28] in the histology of cases of ABMR. This greatly improved the understanding and diagnosis of ABMR. It was called the "footprint" of antibody mediated tissue injury. It soon became a requisite to test for C4d in all transplant allograft biopsies. However, it has been recognised over time that C4d may only be the tip of the iceberg of the humoral process and that it was neither completely specific nor sufficiently sensitive for the diagnosis of ABMR[12, 29, 30].

C4d negative ABMR usually occurs more than 12 months after transplantation, but can occur acutely in highly sensitised patients with persistent DSAs (even after desensitisation).

There have been many theories put forth to explain the presence of microvascular inflamma‐ tion on biopsy and presence of DSAs in circulation, without any evidence of complement deposition. One is the technical issues related to type of fixative used and different methods of C4d detection. Another is that some DSAs are poor at fixing complement. Also, some believe the existence of a complement-independent pathway.[4] Furthermore, it is thought that as a result of treatment of high risk patients, the clinical and histological presentation of ABMR has changed.[3]

#### **4.3. Acceleration of arteriosclerosis**

This phenomenon has been recognised for many decades. It is evidenced by monocytic and lymphocytic inflammation of the intima, myofibroblast proliferation and extracellular matrix deposition causing mild to severe intimal arteritis and compromise of the lumen. It is a major component of graft rejection but thought to be cell mediated. However, in 2003 Banff criteria, the v3 lesions have been classified to reflect probable ABMR. More and more, studies have shown that even v1 and v2 lesions occur in ABMR.[31]

Studies suggest that in DSA-positive patients there is significant acceleration of arteriosclero‐ sis.[11] Pathological examination demonstrated that while there is active ABMR, the intima is hypercellular, laying down new collagen over older (usually originating from donor). Once ABMR is brought under control, the myofibroblasts stop proliferating, and the intima is no longer hypercellular. What is left behind is a lesion no different from simple arteriosclerosis of aging. This is termed "transplant arteriopathy".[11, 32]

Chronic Antibody Mediated Rejection First described in 2001[33], the natural history of chronic humoral rejection is now well known.[12, 29, 34] The presence of DSAs activates the classical complement pathway causing peritubular multilamination and transplant glomer‐ ulopathy. These gradually become irreversible and cause permanent graft dysfunction. The main challenges are when to initiate treatment and how to treat it, as it may be too late to slow or halt the progress of this injury.[34, 35]
