**1. Introduction**

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416 Current Issues and Future Direction in Kidney Transplantation

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2011;72(11):1060-3.

Late graft loss remains a major obstacle to successful long-term kidney allograft transplanta‐ tion. The factors contributing to late graft loss include immunological (cellular and/or antibody mediated injuries) and non-immunological (donor disease, recurrent disease, peri-transplant ischemia, viral infection or drug toxicity) factors (Smith et al., 2006).

For decades, T cells were considered as the primary contributors to acute as well as chronic rejection after organ transplantation.

The role of antibody in rejection of transplanted organs was the subject of debate in the early days of transplantation. Peter Gorer was the first to describe the role of antibody and Peter Medwar championing cell-mediated immunity. Following the death of Gorer's in 1961, the concept of antibody-mediated rejection faded into the background. However, by 1997 demonstration of the relative sensitivity and specificity of C4d staining in peritubular capil‐ laries in identifying antibody mediated rejection raised the hope that a rigorous morphological classification could be devised.

Allo-antibodies to HLA class I or II and other antigens expressed by endothelium cause a variety of effects on renal transplants, ranging from acute to chronic rejection, and even apparent graft acceptance (accommodation). Recognition of these conditions and appropriate therapy requires demonstration of C4d in biopsies, commonly confirmed by tests for circulat‐ ing allo-antibody (Lefaucheur et al., 2010).

Pre-existing (Amico et al., 2009) or post transplant (Cantarovich et al., 2011; Lefaucheur et al., 2010) development of donor specific antibodies (DSA) lead to Acute AMR occurred in 8% of kidney transplant patients. The 5-year graft survivals of patients who had an episode of AMR were significantly worse than that of the remaining transplant population. The relative risk

(RR) for graft loss for patients who had an episode of AMR was around 4 times as compared with patients without AMR. Importantly, even in patients without any episode of AMR, the presence of anti-HLA-DSA on the peak serum was still associated with a significantly lower graft survival as compared with patients without anti-HLA-DSA (Amico et al., 2009; Cantar‐ ovich et al., 2011; Lefaucheur et al., 2010).

During the 12th International Histocompatibility workshop, a multicenter prospective study was initiated to test patients with functioning kidney transplants once for HLA antibodies post-transplantation. The 806 patients without HLA antibodies, had a subsequent 4 year graft survival of 81%, compared with 58% for 158 patients with HLA antibodies [the presence of anti-HLA antibodies led to 5% allograft loss every year; therefore, after 4 years, 20% of the

Current and Future Directions in Antibody-Mediated Rejection Post Kidney Transplantation

http://dx.doi.org/10.5772/55001

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Among 512 patients followed for 1 year post-testing in Sao Paulo, 12% of antibody positive patients lost their grafts, whereas graft failure occurred in only 5.5% of those without HLA antibodies (P=0.03) (Campos et al., 2006). These results have been updated, demonstrating that at 3 years post-transplantation, patients without HLA antibodies had a 94% survival rate compared with 79% for those with HLA class II antibodies (Gerbase-DeLima et al., 2007).

In a large multicentre trial, HLA-specific antibodies were detected in 21% of patients with renal allografts and 14–23% of patients with heart, liver or lung allografts (Terasaki & Ozawa, 2004). Of 2,278 renal-allograft recipients who were followed prospectively, graft failure at 1 year occurred more frequently in patients who developed alloantibodies than in those who did not (8.6% versus 3.0%). Several studies have reported that de novo antibodies that are specific for graft HLA class I and class II molecules are a risk factor for premature graft loss as a consequence of renal and cardiac chronic arteriopathy (Michaels et al., 2003; Pelletier et al.,

For example, during a 5-year follow-up period, donor-reactive antibodies were present in 51% of patients with graft failure compared with 2% of stable control individuals. The presence of antibodies preceded graft failure in 60% of cases (Worthington et al., 2003). Worthington et al (Worthington et al., 2001) showed that among 12 patients who developed ELISA-detected HLA antibodies post-transplantation, 92% of the grafts failed, whereas among the 64 patients who

So, circulating HLA-specific antibodies are typically present months to years before graft dysfunction, indicating that antibody-mediated graft injury might be slow to develop.

The pathogenesis of late renal allograft loss is heterogeneous and difficult to diagnose.

How alloantibody and complement activation promote glomerulopathy, arteriopathy and fibrosis is incompletely clear. Only in the past 7 years, a potential role of alloantibodies for

Alloantibodies are now appreciated as important mediators of acute and chronic rejection,

Alloantibodies preferentially attack a different "location," namely the peritubular and glomerular capillaries, in contrast to T cells, which characteristically infiltrate tubules and

remained negative, only 11% of the grafts failed (P<0.001).

chronically deteriorating graft function has been postulated.

differing in pathogenesis, or "nature," from T cell–mediated rejection.

**3. Pathogenesis and mechanism**

grafts will be lost ]( Terasaki et al., 2007).

2002; Piazza et al., 2001).

arterial endothelium.

The recently described entity of subclinical AMR (Gloor et al., 2006; Haas et al., 2007) in which progressive morphologic lesions are found on biopsy in the absence of overt clinical rejection may account for this different course. A recent study demonstrated that subclinical AMR is a frequent finding in patients with preformed HLA-DSA (31.1% at 3 months) and is associated with worse GFR at 1 year (Loupy et al., 2009). These progressive lesions lead to chronic humoral rejection, first described in 2001 (Regele et al., 2002) and now recognized to be a distinct cause of late graft dysfunction and loss (Gloor et al., 2007; Regele et al., 2002).

Antibody-mediated rejection has become clinically critical because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Although desensitization protocols have enabled transplantation across donor-specific antibody barriers in a growing number of cases (Haas et al., 2007; Jordan, 2006), these protocols are neither consistently efficacious nor standardized. It reflects an incomplete understanding of the pathogenesis of alloantibody-induced injury as a major cause of allograft loss. Furthermore, patients treated with these modalities persist in having a high risk of multiple AMR episodes and lower graft long term survival compared to antibody free patients.
