**5. Acute and sub-acute rejection**

Many studies have pointed out that the long term outcomes of transplanted kidneys that underwent episodes of AR are inferior compared to those that did not. The long term outcomes are even worse if the episodes of rejection have been multiple or if the acute rejection occurs late, usually meaning more than 6 months after the transplant. The obvious correlation here is that many times, non-compliance with immunosuppressive medications would be a confounding factor. What is also an obvious factor is that each episode of rejection leaves the transplanted organ with progressively increasing amounts of interstitial fibrosis and tubular atrophy with a cumulative effect of functional decline, eventually resulting in organ failure.

However, the incidence of AR has markedly declined, with the actual incidence within the first year being less than 10% (USRDS, 2008). This decrease has not translated into an improvement in the overall graft survival or the median survival time of renal allografts. An explanation to this phenomenon may be that even when there is no acute allograft dysfunction in terms of worsening creatinine clearance, proteinuria or hypertension, there is an ongoing inflammatory infiltration that leads to structural damage and eventual scarring of the renal parenchyma, termed as subclinical rejection. This entity is usually discovered by protocol biopsies, which are not performed in a cross-sectional manner. This means that an

Yet another phenomenon observed in the context of circulating antibodies is that sometimes, there may be no evidence of graft destruction at all, even with varying degree of C4d deposition. This process, termed accommodation, has been the focus of research in recent years, with a wealth of insight provided by transplantation of organs across the barrier of ABO incompatibility. Though anti-A or B isoagglutinin reappear after transplant, they can co-exist without precipitating rejection (Gonzalez-Strawinski et al., 2008). Interestingly, C4d deposition can be observed but, compatible with other observations, does not necessarily mean that CAMR is taking place. Understanding the mechanism by which the graft attains this ability to remain "non-reactive" despite the presence of antibodies circulating against it is of great interest as it can be therapeutically mimicked when DSAs are known to exist that would otherwise lead to an immunologically mediated rejection of the graft. Accommodated grafts have been found to have changes in the cells of the endothelium and that are believed to help in the adaptation to the presence of antibodies. These changes include increased expression of bcl-xL, (Salama et al. 2001), increased muc-1 expression (Park et al. 2003) and increase in the expression of indolamine-2,3-dioxygenase (Minnei et

In conclusion, CAMR occurs slowly, with the first step being the development of DSA, followed by an immunological reaction that *may* result in the deposition of C4d, the resultant development of visible pathological changes characteristic of CAMR and then eventual graft loss. The speed at which these events occur is variable and the challenge is not just limited to the difficulty in diagnosis, but also in terms of therapy. In the future, the main strategies to counteract the risk for CAMR will be focused on screening for the development of new DSA, following the titers of known DSAs and correlating them with the function of the transplanted kidney. Also, as we learn more about the adaptive capabilities that lead to accommodation, strategies will likely be developed to mimic them

Many studies have pointed out that the long term outcomes of transplanted kidneys that underwent episodes of AR are inferior compared to those that did not. The long term outcomes are even worse if the episodes of rejection have been multiple or if the acute rejection occurs late, usually meaning more than 6 months after the transplant. The obvious correlation here is that many times, non-compliance with immunosuppressive medications would be a confounding factor. What is also an obvious factor is that each episode of rejection leaves the transplanted organ with progressively increasing amounts of interstitial fibrosis and tubular atrophy with a cumulative effect of functional decline, eventually

However, the incidence of AR has markedly declined, with the actual incidence within the first year being less than 10% (USRDS, 2008). This decrease has not translated into an improvement in the overall graft survival or the median survival time of renal allografts. An explanation to this phenomenon may be that even when there is no acute allograft dysfunction in terms of worsening creatinine clearance, proteinuria or hypertension, there is an ongoing inflammatory infiltration that leads to structural damage and eventual scarring of the renal parenchyma, termed as subclinical rejection. This entity is usually discovered by protocol biopsies, which are not performed in a cross-sectional manner. This means that an

al., 2008) in the glomerular and PTC endothelium.

in vivo to prolong the renal graft survival.

**5. Acute and sub-acute rejection** 

resulting in organ failure.

inflammatory response, which is not very severe, but in most cases chronic does occur and over time results in graft loss. There has been a clear demonstration that subclinical rejection leads to an early development of CAN and graft loss particularly if there is coexisting interstitial fibrosis and tubular atrophy (Cosio et al, 2005; Nankivell et al., 2004, Moreso et al., 2006; Shishido et al., 2003; Veronese et al. 2004). It is also important to stress that while there may not be a significant functional deterioration at the time sub-clinical rejection is diagnosed, many times the actual injury as demonstrated by protocol biopsies may be of high grade. One study categorized the results of a cohort of protocol biopsies and revealed that 1 out of 3 of these cases has interstitial acute rejection Grade 1 and 2 out of 3 were classified as borderline changes (Nankivell et al., 2004). There has also been a repeated demonstration that the degree of infiltration seen in protocol biopsies revealing subclinical rejection has correlated to the degree of HLA incompatibility further proving that this infiltration is driven by an immunological phenomenon. There are instances when there is clear histological demonstration of infiltration in the renal parenchyma with no rise in serum creatinine implying that there is no functional decline. This further elaborates the unreliability and underestimation of renal dysfunction offered by measuring serum creatinine level (Kaplan et al., 2003; Levey et al., 1999).

This raises the question of whether protocol biopsies should be performed on a regular interval. While some studies have demonstrated a clear benefit in terms of a decreased incidence of AR and lower serum creatinine at two years after the kidney transplant (Rush et al., 1998), there have been other studies that indicate that treatment of subclinical infiltration on the basis of a protocol biopsy may not have significant improvement in the long term and may further expose the patient to increased amounts of immunosuppression and further the risk of CNI toxicity. Therefore, with the currently existing data, most centers do not perform protocol biopsies on all patients; however, experts do recommend performing protocol biopsies on at least some of the patients that are considered high risk where an inflammatory infiltrate likely means a clinical rejection. If left untreated, it will likely result in an accelerated course towards CAN and the eventual loss of function of the allograft.
