**2. Pathological classification**

The 8th Banff Conference on Allograft Pathology, held in 2005 (Solez et al, 2007) focused on removing the term CAN as a pathological entity. This term was first used in 1991 when it replaced the term 'chronic rejection'. While it was successful in removing the notion that an immunologically mediated mechanism was in all instances the reason for the graft to slowly deteriorate, its use as a generic term came in the way of ascertaining a specific diagnosis and identification of the actual pathological process at play.

While the pathological findings of 'interstitial fibrosis and tubular atrophy' (IF/TA) are common in most instances of chronic allograft injury, other features can sometimes point towards the actual disease process. For example, arterial fibrointimal thickening with duplication of internal elastica (fibroelastosis), arteriolar and small artery hyalinosis, glomerulosclerosis, along with IF/TA can be a manifestation of chronic hypertension (Olson et al, 1998); hyaline arteriolar changes, sometimes with peripheral hyaline nodules, and IF/TA either in 'striped' ischemic or diffuse form can be secondary to calcineurin inhibitor (CNI) toxicity (Morozumi et al, 2004, Basauschina et al, 2004 and Mihatsch et al, 1995); IF/TA with relative glomerular sparing, dilated tubules, atubular glomeruli and intratubular Tamm–Horsfall protein casts with extravasation into the interstitium may suggest chronic obstruction (Klahr et al, 2003); IF/TA with chronic inflammation, intranuclear inclusions highlighted on immunostaining for the SV40 large T antigen can be due to BK virus infection (Drachenberg et al, 2005), a polyoma virus that may infect the tubular cells in immune suppressed patients. In other instances, recurrent or de novo vascular or glomerular diseases may lead to glomerulosclerosis along with IF/TA.

This leads to a new category of "interstitial fibrosis and tubular atrophy, no evidence of any specific etiology" to replace "CAN". There is further sub-categorization within the category of "IF/TA, no evidence of any specific etiology" and this is based on amount of interstitial fibrosis, and the degree of atrophy and loss of tubules. It is described as mild (Grade I), moderate (Grade II) and severe (Grade III) determined by <25%, 25-50% and >50% of the cortical area involved respectively (Salez et al, 2007). The pitfall to this classification is that the degree of IF/TA in a renal graft is yet to be shown to correlate with the prognosis and overall graft survival. This is therefore an area where protocol biopsies done at previously determined time intervals, and the correlation of these results with graft survival in the long term, will provide invaluable prognostic information.

In the same revision of the Banff criteria, there was also the introduction of the subcategories of 'chronic active antibody mediated rejection' and 'chronic active T-cell mediated rejection' within the categories of antibody mediated rejection (AMR) and T-cell mediated rejection respectively. These were introduced to highlight the features of arterial and capillary

poor graft quality, ischemia and reperfusion injury, delayed graft function, recurrent or de novo kidney disease, hypertension, diabetes, obstruction, infection, renal artery stenosis and calcineurin inhibitor toxicity. It has been recently suggested that the autoimmunity may also contribute to the post-transplant allograft injury (Dinavahi et al., 2011; Porcheray et al., 2010; Vendrame et al.,2010). Here, we will focus our discussion on the allo-immunological injury, as this mechanism has been well established and its importance has been increasingly

The 8th Banff Conference on Allograft Pathology, held in 2005 (Solez et al, 2007) focused on removing the term CAN as a pathological entity. This term was first used in 1991 when it replaced the term 'chronic rejection'. While it was successful in removing the notion that an immunologically mediated mechanism was in all instances the reason for the graft to slowly deteriorate, its use as a generic term came in the way of ascertaining a specific diagnosis and

While the pathological findings of 'interstitial fibrosis and tubular atrophy' (IF/TA) are common in most instances of chronic allograft injury, other features can sometimes point towards the actual disease process. For example, arterial fibrointimal thickening with duplication of internal elastica (fibroelastosis), arteriolar and small artery hyalinosis, glomerulosclerosis, along with IF/TA can be a manifestation of chronic hypertension (Olson et al, 1998); hyaline arteriolar changes, sometimes with peripheral hyaline nodules, and IF/TA either in 'striped' ischemic or diffuse form can be secondary to calcineurin inhibitor (CNI) toxicity (Morozumi et al, 2004, Basauschina et al, 2004 and Mihatsch et al, 1995); IF/TA with relative glomerular sparing, dilated tubules, atubular glomeruli and intratubular Tamm–Horsfall protein casts with extravasation into the interstitium may suggest chronic obstruction (Klahr et al, 2003); IF/TA with chronic inflammation, intranuclear inclusions highlighted on immunostaining for the SV40 large T antigen can be due to BK virus infection (Drachenberg et al, 2005), a polyoma virus that may infect the tubular cells in immune suppressed patients. In other instances, recurrent or de novo

vascular or glomerular diseases may lead to glomerulosclerosis along with IF/TA.

This leads to a new category of "interstitial fibrosis and tubular atrophy, no evidence of any specific etiology" to replace "CAN". There is further sub-categorization within the category of "IF/TA, no evidence of any specific etiology" and this is based on amount of interstitial fibrosis, and the degree of atrophy and loss of tubules. It is described as mild (Grade I), moderate (Grade II) and severe (Grade III) determined by <25%, 25-50% and >50% of the cortical area involved respectively (Salez et al, 2007). The pitfall to this classification is that the degree of IF/TA in a renal graft is yet to be shown to correlate with the prognosis and overall graft survival. This is therefore an area where protocol biopsies done at previously determined time intervals, and the correlation of these results with graft survival in the long

In the same revision of the Banff criteria, there was also the introduction of the subcategories of 'chronic active antibody mediated rejection' and 'chronic active T-cell mediated rejection' within the categories of antibody mediated rejection (AMR) and T-cell mediated rejection respectively. These were introduced to highlight the features of arterial and capillary

recognized in the pathogenesis of CAN.

identification of the actual pathological process at play.

term, will provide invaluable prognostic information.

**2. Pathological classification** 

changes, believed to be pathognomonic of an immunologically mediated chronic allograft injury which would also have IF/TA, in other words identifying true chronic rejection. The need for introducing the subcategory of chronic antibody mediated rejection (CAMR) was based on the abundantly available literature that highlighted the presence of complement fragments (C4d) positivity (explained in more detail in Role of B cells and DSA) and the presence of anti-HLA antibodies in transplant patients correlating with the chronic failing of the allografts. When these are seen in the presence of pathological changes specific to an active process of AMR taking place, that subset of patients could be safely assumed to be undergoing an immunologically mediated, in specific humorally mediated reaction. The diagnostic criteria therefore for 'CAMR' are as follows;

Morphological features of duplication or 'double contours' in glomerular basement membranes, and/or peri-tubular capillary basement membrane multi-layering (PTCBMML) and/or IF/TA with or without PTC loss, and/or fibrous intimal thickening in arteries without duplication of the internal elastica


The pathological significance of these findings and their role in causing deterioration in graft function will be highlighted in the section "Role of B-cells and DSA" below. Transplant glomerulopathy of membrano-proliferative glomerular nephritis (MPGN) pattern should be distinguished from the immune complex-mediated MPGN that is frequently associated with hepatitis C infection or due to recurrent or de novo glomerular disease. They appear similar (MPGN) on light microscopy, but their distinction can be made by electron microscopy, as transplant glomerulopathy does not have immune-complex deposits on the glomerular basement membrane.

'Chronic active T-cell mediated rejection' is described as a subcategory of "T-cell mediated rejection" and it denotes the presence of chronic allograft arteriopathy with arterial intimal fibrosis along with mononuclear cell infiltration and fibrosis and the formation of neointima. These changes and their role will also be described in more detail in the section "Role of T-cell" below.
