**8. Acceptable HLA-mismatch and highly sensitized transplant candidates**

Highly sensitised transplant candidates (defined as those having a panel reactive antibody [PRA] level of >80%) on the deceased donor transplant wait-list are less likely to receive donor kidneys (greater likelihood of obtaining a positive complement-dependent cytotoxicity [CDC] cross-match result with any given donor) and have a much longer wait-list time compared to unsensitized transplant candidates, resulting in a greater risk of mortality whilst remaining on the transplant wait-list [93]. In Australia, highly sensitized transplant candidates represent approximately 5% of the wait-listed candidates and are more likely to wait on average twice as long as unsensitized transplant candidates despite an increase in the number of deceased donors over time (202 donors in 2006 compared to 309 donors in 2010) [6].

Although HLA matching has traditionally been performed at the broad antigen level, a model considering cross-reacting groups (CREGs) may increase the probability of identifying more compatible kidneys for ethnic minorities and highly sensitized transplant candidates. HLA antigens comprise of multiple serologic epitopes made of polymorphic amino acid residues, and it is these structures and their conformation and position that determine antibody

The Luminex platform determines specificity and quantifies anti-HLA antibodies present in potential transplant candidates and is used in Australia to define unacceptable class I HLAmismatches. Although it may be logical to consider Luminex-define DSA with MFI of <500 as acceptable mismatch, the utlilization of this technique or the appropriate thresholds of

In highly sensitized transplant candidates, the identification of acceptable HLA-mismatch has been shown to improve their transplant potential by reducing the number of HLA-mismatches therefore identifying additional donors likely to produce a negative CDC cross-match.

Successful acceptable HLA-mismatch programs have been implemented in many countries, including Europe, United Kingdom and United States [45, 114-116]. Eurotransplant Acceptable Mismatch Program was established in mid 1970 to improve the transplant potential of highly sensitized transplant candidates. Over the ensuing decade, eleven other similar programs were introduced throughout Europe [103]. Although there is considerable variation in PRA cut-off to define highly sensitized transplant candidates, it is generally accepted that PRA >80% may be the most appropriate cut-off. Table 2 highlights the results of the established acceptable

**Scheme Initiation Reference Eligibility Outcomes/Activity**

Feb 1984 [*106*] PRA"/>85%

1985 [*107*] PRA"/>80%

1985 [*100*] PRA≥85%

Jan 1994 [*108*] PRA≥40%

(historic or current sera)

(current sera)

(historic or current sera)

(current sera)

• 65% graft survival at 1year • 42% transplanted within 1year

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• 5-year graft survival comparable to unsensitized recipients (59% vs 60%)

• 2-year graft survival comparable to unsensitized recipients (87%) • 45% transplanted in 1year, mean 8.9 months reduction in mean wait time

• 2-year graft survival comparable to unsensitized recipients (86% vs 88%)

Luminex-determined acceptable mismatch remain unknown [102].

**9. Acceptable HLA-mismatch programs**

mismatch programs.

UK Transplant SOS Scheme

Collaborative Transplant Study Highly Immunized Trial

Eurotransplant Acceptable Mismatch Program (ET:ACMM)

South Eastern Organ Procurement Foundation High Grade HLA Match

PRA – panel reactive antibody, HLA – human leukocyte antigen

**Table 2.** Description of allocation schemes based on acceptable HLA-mismatch.

(UKT:SOS)

(CTS:HIT)

algorithm (SEOPF:HGM)

HLA – human leukocyte antigen, UNOS – United Nation Organ Sharing, T - triplets.

**Figure 5.** Impact of HLA-A, -B triplet (T) matching on 5-year graft survival rates in zero-HLA-DR-mismatched kidney transplants in a cohort of United Nation of Organ Sharing (UNOS) renal transplant recipients between 1987 and 1999 (adapted from *Duquesnoy et al* Transplantation 2003) [101].

accessibility, recognition, and subsequent reactivity [94]. Almost 200 class I and II epitopes have been defined by Luminex technology [95]. Some epitopes are shared across different HLA alleles while some are unique to single or more restricted numbers of HLA alleles. While there are considerable differences in HLA antigen frequencies between different ethnic groups, CREGs are more evenly distributed [96].

The concept of acceptable HLA-mismatch identifies mismatched HLA-antigens that could be considered as compatible at a structural or functional level. It is based on the principle that each HLA antigen is structurally unique and that an individual cannot mount an immuno‐ logical response against an epitope expressed by their own HLA, i.e. one cannot react against shared 'self' epitopes [105, 106]. It has been demonstrated that such acceptable HLA-mis‐ matches would result in a negative CDC cross-match and therefore allow transplantation to safely proceed [97, 98].

Acceptable HLA-mismatches can be identified using HLAMatchmaker or the Luminex platform. HLAMatchmaker is a computer algorithm that regards each HLA antigen as a string of polymorphic amino acid configurations in antibody-accessible positions (epitopes) formed by triplets or eplets [99, 100]. For any given set of HLA antigens, HLAMatchmaker can define the number of triplet or eplet mismatches present against any foreign HLA antigen and hence define the HLA antigens that are mismatched at the broad antigen level but matched at the eplet level, i.e. acceptable HLA-mismatches. Graft outcomes of HLAMatchmaker-identified 0-2 triplet-mismatched kidney transplant recipients are similar compared to recipients with 0 HLA-mismatch at the HLA-A, -B and –DR loci (Figure 5) [101]

The Luminex platform determines specificity and quantifies anti-HLA antibodies present in potential transplant candidates and is used in Australia to define unacceptable class I HLAmismatches. Although it may be logical to consider Luminex-define DSA with MFI of <500 as acceptable mismatch, the utlilization of this technique or the appropriate thresholds of Luminex-determined acceptable mismatch remain unknown [102].

In highly sensitized transplant candidates, the identification of acceptable HLA-mismatch has been shown to improve their transplant potential by reducing the number of HLA-mismatches therefore identifying additional donors likely to produce a negative CDC cross-match.
