**6. Degree of HLA mismatch**

Three pairs of human leukocyte antigens (HLA) loci A, B and DR are traditionally used for organ allocation. They exist on chromosome 6 with both alleles inherited from either parent are co-expressed, resulting in any individual having 6 antigens. There is tremendous amount of variation in the actual antigen that is coded by each of these loci among individuals as this gene exhibits what is known as polymorphism. With advances in molecular biology more than 230 polymorphisms have been identified for HLA-A, more than 470 for HLA-B and more than 380 for HLA-DR. Their relevance stems from the fact that these antigens are expressed on the surface of all cells and are the major barrier to transplantation. Because of the way our immunological system is designed, the recognition of self versus foreign antigens is mediated through these HLA antigens. Hence when foreign tissue is introduced to the immune system of a host and it is recognized as foreign, it is due to lack of tolerance that the host has developed towards its own variety of HLA antigens.

As these antigens are carried on fixed loci, their inheritance follows a Mendelian pattern, and a combination of HLA-A, B and DR is inherited by an individual from both parents.

The Allo-Immunological Injury in Chronic Allograft Nephropathy 411

to be in need of kidney transplantation should be transfused with caution during their course of CKD as well as when they are on renal replacement therapy to keep sensitization

Due to lack of the Y chromosome in women, antigens coded for by the Y chromosome are recognized as foreign when organ transplantation occurs from a male donor to a female recipient (McGee et al., 2010, 2011). While this does not manifest immunologically as strongly as HLA incompatibility, it does have an effect of having shorter graft survival when an organ is taken from a male donor and transplanted to a female recipient (McGee et al., 2010). This effect is more strongly noted among bone marrow transplants, but is also present to some degree in solid organ transplants such as the kidney (Gratwohl et al., 2008). The decreased survival of male to female donation compared to female to male donation is seen despite the fact that in most instances a higher nephron mass of a male donor kidney is

The significant improvement in the short-term graft survival has not transformed into a much better long-term graft survival. CAN is an important cause of graft loss and it represents a complex process culminating immunological and non-immunological injuries. The occurrences of overt acute rejections, either cellular, humoral or both, in the early stage driven by allo-immunity can have an important bearing on the long term immunological milieu that prevails and hence influences the graft survival. Sub-clinical rejection and/ or chronic rejection from inadequate immunosuppression are frequently undiagnosed and untreated. Persistent DSA or de novo development of DSA after kidney transplant is increasingly recognized as an independent and detrimental factor for transplant glomerulopathy. Other than allo-reactivity, there are emerging data suggesting that the preexisting or de novo developing autoimmunity, mediated by either auto-antibodies and/or autoreactive T cells, may also cause post-transplant allograft injury (Dinavahi et al., 2011; Porcheray et al., 2010; Vendrame et al.,2010). Therefore, to appropriately identify and address the actual disease process, knowledge of the ongoing pathogenesis is needed in order to improve the long-term graft survival. From allo-immunological standpoint, it may include optimizing HLA match, avoiding sensitization, timely detecting and treating AR episodes, and maintaining adequate levels of immunosuppression to prevent the

development of DSA, sub clinical rejection and chronic rejection of allografts.

mice. *ProcNatlAcadSci USA*; Vol. 90, pp. 3373–3377

*Transplant Proc*; Vol. 36 (Suppl 2S), pp. 229S–233S

Auchincloss H, Lee R, Shea S et al. (1993). The role of 'indirect' recognition in initiating

Bal V, McIndoe A, Denton G et al. (1990). Antigen presentation by keratinocytes induces

Busauschina A, Schnuelle P, van der Woude FJ. (2004) Cyclosporine nephrotoxicity.

tolerance in human T cells. *Eur J Immunol*; Vol. 20, pp. 1893–1897

rejection of skin grafts from major histocompatibility complex class II-deficient

transplanted into a smaller body of a female recipient.

at minimum.

**7. Gender** 

**8. Summary** 

**9. References** 

Hence, when identical twins or siblings, who have the same HLA antigens donate to each other, the survival is superior compared to randomly matched cadaveric donors, with an intermediate level of graft survival seen when parents or genetically non-identical siblings donate where one of the haplotypes are matched. In population based programs, which rely predominantly on cadaveric donation, finding single or double haplotype match is obviously not very common. The goal is to find a donor and recipient combination that has zero to minimum mismatches, meaning the least amount of HLA antigens expressed on the surface of donor cells that are not present in the recipient. There has also been recognition of the fact that there are some HLA mismatches that are more significant than others, for example having a DR mismatch is now known to be much more detrimental to graft survival than having a mismatch of the A and B antigens (Coupel et al., 2003; Opelz 1985).

In the earlier years of transplantation, having HLA mismatches led to a high incidence of early rejection and eventual graft failure. With the modern and more potent immunosuppressive agents used today, such episodes are rare in the first year. However, despite the immune suppression and the low incidence of AR in the first year, the long term survival of grafts from well matched (6 antigen match or zero mismatch) donors have a longer survival than from those who are not as well matched and according to recent analysis of the national database in the United States (OPTN/SRTR, 2008) this effect is seen in living donors and deceased donors of both extended and non-extended criteria. Despite the above stated evidence pointing towards better survival among well matched organ allocation, only 13% of the organs allocated in the US are well matched. (Takemoto et al., 2000). The main reasons are that despite the large numbers of people on the waiting list, well matched organs are difficult to find. When they are found, the absolute match may be in a different part of the country. If organ allocation is done by HLA only, not considering geographical location, the cold-ischemia time increases as the organ is transported. As the cold-ischemia time increases, chances of delayed graft function increase and overall it negatively affects outcomes and costs. According to an analysis, the added advantage of a zero mismatch is lost once the cold-ischemia time exceeds 36 hours (Lee et al., 2000).

Exposure to foreign antigens whether in the form of organ donation, blood transfusion and in the case of women, through child birth, leads to development of antibodies that are reactive towards these antigens, a process referred to as "sensitization". A measure known as the Panel Reactive Antibodies (PRA) estimates the degree of sensitization that a potential recipient has and this reflects the likelihood of having difficulty finding an organ to which the recipient does not have preformed antibodies against. Pre-existing DSA or developing de-novo DSA in the post-transplant period predisposes the recipient to develop AMR. Even if there is no overt episode of AMR clinically, the graft survival is still poor, which is explained by development of transplant glomerulopathy from CAMR.

Strategies to prevent CAN due to HLA incompatibility include matching donors and recipients with minimal mismatches, cross matching to ensure that there is no DSA. If DSA are present, various desensitization protocols utilizing intravenous immunoglobulin and plasmapheresis can be used to decrease the likelihood of AMR. In the post transplant period, a watchful evaluation of kidney function with close monitoring of serum markers as well as urinalysis should be kept to recognize early development of AMR and CAMR. The threshold to evaluate renal dysfunction with kidney biopsy should be low in patients at increased risk of rejection due to HLA incompatibility. In the outset, patients who are likely to be in need of kidney transplantation should be transfused with caution during their course of CKD as well as when they are on renal replacement therapy to keep sensitization at minimum.
