**1. Introduction**

400 Chronic Kidney Disease

[69] Zoccali C, Benedetto FA, Tripepi G, Cambareri F etal.Nocturnal Hypoxemia, night-day

Int, 53:1078-84, 1998

arterial pressure changes and left ventricular geometry in dialysis patient.Kidney

Progressive loss of renal allograft function after the first year of kidney transplant is often referred to as chronic rejection, transplant nephropathy, transplant glomerulopathy or chronic allograft nephropathy (CAN) and the use of these terms is often interchangeable. Clinically, it is usually diagnosed by a slowly rising serum creatinine level, increasing proteinuria and worsening hypertension (Zhang et al., 2004). CAN is the second most common cause of graft loss after the leading cause, death with a functioning graft (DWFG) (Zhang et al., 2004). According to estimates, 25-30% of patients currently awaiting kidney transplant have received a transplant before.

With the widespread usage of induction agents and the advancements in immunosuppressive medications, the first year outcomes after kidney transplant have shown steady improvement. In the United States, the incidence of acute rejection (AR) in the first year is below 10% (United States Renal Data System [USRDS]) while the unadjusted graft survival is 96%, 92% and 85% for living, deceased and extended criteria deceased donors respectively (Organ Procurement and Transplant Network/Scientific Registry of Transplant Recipients [OPTN/SRTR], 2008).

In the long term though, the survival of grafts has shown very little improvement over the past decade. The 5 year graft survival is reported at 81%, 71% and 55% for living, deceased and extended criteria deceased donors in the time interval of year 2000-2005. This, in comparison, is hardly different from the 79%, 68% and 51% reported in the interval of 1994-1999 (OPTN/SRTR, 2008). The median graft survival years for all kidney transplants, according to a report published in 2004 has changed little when comparing transplants performed in the years 1988 through 1995, ranging between 7.5 to 8.0 years. (Meier-Kriesche et al, 2004)

An overall shortage of organs and the high cost of providing any form of renal replacement therapy inclusive of a kidney transplant, calls for attention into making efforts for kidney transplants to last longer. This would entail looking into the pathological processes that result in the eventual failure of grafts, delineating as far as possible one process from the other, and examining immunological and non-immunological determinants that may be targeted with the eventual goal of adopting strategies that may help in prolonging the survival of renal allografts (Zhang et al, 2004). The non-immunological factors may include

The Allo-Immunological Injury in Chronic Allograft Nephropathy 403

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

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

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

'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

The introduction of an "allograft" into an immunocompetent individual would typically result in a process of recognizing the graft tissue as foreign "allorecognition" and the initiation of what is known as an "alloresponse", invariably resulting in tissue inflammation, architectural distortion and infiltration by T-cells that are responsive to the graft resulting in loss of function and eventual failure of the graft, a process we call acute cellular rejection. This occurs after a number of steps taking place at the molecular and cellular level, steps that have been recognized and become the target of therapy in order to prevent rejection.

Allorecognition can occur by three well-described mechanisms referred to as direct, indirect and the semi direct pathways. (Safinia et al, 2010). In the direct pathway recipient T cells recognize intact allogeneic major histocompatibility complex or MHC-peptide complexes expressed by foreign cells, while in the indirect pathway T cells recognize peptides derived from allogeneic MHC proteins presented by antigen-presenting cell and finally the semi

diagnostic criteria therefore for 'CAMR' are as follows;

1. C4d deposition in the peri-tubular capillaries (PTC) 2. The presence of donor specific antibodies (DSA)

without duplication of the internal elastica

basement membrane.

"Role of T-cell" below.

**3. Role of T cells** 

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 recognized in the pathogenesis of CAN.
