**4. Effect of HLA-mismatches and renal transplant outcomes**

Large registry reports including analysis from the Collaborative Transplant Study (CTS) and more recently from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry have consistently demonstrated a strong association between HLA-matching at the HLA-A, B and DR loci and graft and patient outcomes, independent of donor type, initial immunosuppression, transplant era and even the presence of DSA [46-48].

The advantage of improved HLA-matching in reducing acute rejection risk has been demon‐ strated predominantly in renal transplant recipients receiving cyclosporine-based immuno‐ suppressive regimen [49, 50]. Recent retrospective single centre study of live and deceased donor renal transplants has demonstrated that HLA-mismatches remained an important determinant of acute rejection risk in renal transplant recipients receiving quadruple immu‐ nosuppression involving the use of interleukin-2 receptor antibody induction, tacrolimus, mycophenolate mofetil and corticosteroids [51]. In this study, increasing number of HLA mismatches was an independent predictor of acute rejection (OR 1.65 for every single HLAmismatch; 95% CI: 1.15 to 2.38; P=0.007), with HLA-mismatches at the HLA-DR locus associ‐ ated with the highest risk of acute rejection compared to mismatches at the HLA-A and HLA-B loci in the adjusted model. Analysis of the CTS data of 135,970 deceased donor renal transplant recipients demonstrated that the effect of HLA-mismatches on acute rejection risk remained highly significant over two consecutive decades (1985-1994 vs 1995-2004), inde‐ pendent of 'intention to treat' immunosuppressive regimen [47]. Similarly, recent analysis of ANZDATA registry of live and deceased donor renal transplants between 1998 and 2009 demonstrated that the association between HLA-mismatches and acute rejection risk appeared to be independent of transplant era and initial immunosuppression, but this association appeared to be much stronger for live-donor transplants compared to deceased donor transplants (Figure 3A). The reduced benefit of 0-HLA-mismatched kidneys in recipients of deceased compared with live donor kidneys may be explained by the presence in unrelated deceased donors of apparently matched but actually mismatched splits of antigens, which is less frequently observed in biologically related living donors [46]. However, the association between HLA mismatches and rejection was not linear, with the greatest benefit of HLA matching appeared to be confined to those with <4 HLA mismatches [46, 47].

0 1 2 3 4 5 6

**HLA-mismatches Live donor Deceased donor**

1.00 4.00 (2.38, 6.67)\* 4.17 (2.71, 6.67)\* 5.26 (3.33, 7.69)\* 7.14 (4.76, 11.11)\* 7.69 (4.76, 11.11)\* 8.33 (5.00, 12.50)\*

Reference level:HLA=0 and Live donor HLA mismatches

1.00 1.19 (0.79, 1.79) 1.47 (1.01, 2.13)\* 1.54 (1.04, 2.27)\* 2.13 (1.43, 3.12)\* 1.96 (1.33, 2.86)\* 2.38 (1.56, 3.57)\*

**Odds ratio plot (95% CI)**

http://dx.doi.org/10.5772/54747

353

The Evolution of HLA-Matching in Kidney Transplantation

0

2

4

6

Odds ratio

(a) (b)

**Figure 3.** (a) Odds ratio plot of HLA mismatches and acute rejection according to donor type (reference live donor 0 HLA mismatch) and corresponding table of the adjusted odds ratio between HLA mismatches and acute rejection ac‐ cording to donor type (reference live or deceased donor 0 HLA mismatch; adapted from *Lim WH et al* Clin Transplant 2012) [46]. (b) Kaplan–Meier survival curve of overall graft failure according to the number of HLA mismatches with corresponding numerical table of the number at risk at 0, 4 and 8 years post-transplant (adapted from *Lim WH et al*

The association between acute rejection and graft survival appears well established. In the study by *Wissing et al*, the authors had shown rejection within the first year post-transplant was independently associated with a significant reduction in overall (57% vs 83%; p=0.0004) and death-censored graft survival (63.5% vs 91.2%; p<0.0001) [51], a finding corroborated by

Although HLA-DR mismatches appear to be of greater importance in predicting graft outcomes compared to HLA-AB mismatches, the current kidney allocation algorithm in Australia specifically favours fully HLA-DR matched recipients but still takes into account HLA-AB matching, therefore confers an appropriate concession to allow satisfactory HLAmatching but avoiding discrimination to potential recipients with rare HLA combinations as HLA-DR locus has fewer polymorphisms compared to HLA-AB loci [58]. Previous studies have demonstrated that allocation based predominantly on HLA-DR matching, as imple‐ mented in the United States, may eliminate any advantage of HLA-AB matching but this remains controversial [59, 60]. Analysis of Scientific Registry of Transplant Recipients (SRTR) of 108,701 deceased donor renal transplant recipients demonstrated that the elimination of allocation priority for HLA-B mismatches improved the transplant potential of ethnic minor‐ ities and this policy had achieved comparable renal allograft survival compared to historical graft outcomes prior to the change in allocation policy [61]. Although the presence of HLA-

Clin Transplant 2012) [46].

ANZDATA registry analysis [46].

8

10 12 Donor Type Live Deceased

Large retrospective studies have consistently demonstrated the importance of HLA-matching in determining deceased donor renal allograft survival [52-54]. Analysis of the United Net‐ work for Organ Sharing (UNOS) registry between 1991 to 1997 demonstrated an 11% reduc‐ tion in 3-year graft survival rate (p<0.001) between transplants involving 6 compared to 0 HLAmismatches, with the most discernible difference in survival was observed between recipients with 0 to 1 HLA-mismatch [55]. In the UNOS study, the association between HLA-mismatches andreducedgraft survivalappearedtobe relatedtomismatchesattheHLA-DRlocuswithinthe firstyearpost-transplant,whereasmismatchesattheHLA-ABlociweremoreimportantbeyond the first year post-transplant. However, the association between HLA-mismatches and graft survival in the era of modern immunosuppression remains contradictory [56]. Analysis of the CTSdatademonstratedthattheimportanceofHLA-matchingongraftoutcomesremainedstrong during the two decades of 1985-1994 and 1995-2004, suggesting that association between HLAmismatches and graft survival remains robust in the era of modern immunosuppression [47]. Unlike the other large registry studies that had focused on deceased donor renal transplants, the study by *Lim WH et al* using ANZDATA registry data evaluated both live and deceased donor renal transplants. Similarly, the authors demonstrated a strong association between HLAmismatchesandoverallgraft survivalforbothliveanddeceaseddonorrenaltransplants (Figure 3B),especiallybetweenthosereceiving0-HLA-mismatchedkidneyscomparedtothosereceiving ≥1 HLA-mismatched kidneys [46]. In contrast, analysis of the UNOS data suggested that the relative importance of HLA-mismatches and reduced graft survival may have diminished in recent years, whereas other factors such as donor age retained their statistical significance over timepromptingthesuggestionthatkidneyallocationalgorithmsbasedpredominantlyonHLAmatching should be modified [57]. However, this study focused on era between 1994 and 1998 whereby the use of induction therapy and/or tacrolimus was limited.

**Odds ratio plot (95% CI)**

nosuppression involving the use of interleukin-2 receptor antibody induction, tacrolimus, mycophenolate mofetil and corticosteroids [51]. In this study, increasing number of HLA mismatches was an independent predictor of acute rejection (OR 1.65 for every single HLAmismatch; 95% CI: 1.15 to 2.38; P=0.007), with HLA-mismatches at the HLA-DR locus associ‐ ated with the highest risk of acute rejection compared to mismatches at the HLA-A and HLA-B loci in the adjusted model. Analysis of the CTS data of 135,970 deceased donor renal transplant recipients demonstrated that the effect of HLA-mismatches on acute rejection risk remained highly significant over two consecutive decades (1985-1994 vs 1995-2004), inde‐ pendent of 'intention to treat' immunosuppressive regimen [47]. Similarly, recent analysis of ANZDATA registry of live and deceased donor renal transplants between 1998 and 2009 demonstrated that the association between HLA-mismatches and acute rejection risk appeared to be independent of transplant era and initial immunosuppression, but this association appeared to be much stronger for live-donor transplants compared to deceased donor transplants (Figure 3A). The reduced benefit of 0-HLA-mismatched kidneys in recipients of deceased compared with live donor kidneys may be explained by the presence in unrelated deceased donors of apparently matched but actually mismatched splits of antigens, which is less frequently observed in biologically related living donors [46]. However, the association between HLA mismatches and rejection was not linear, with the greatest benefit of HLA

352 Current Issues and Future Direction in Kidney Transplantation

matching appeared to be confined to those with <4 HLA mismatches [46, 47].

whereby the use of induction therapy and/or tacrolimus was limited.

Large retrospective studies have consistently demonstrated the importance of HLA-matching in determining deceased donor renal allograft survival [52-54]. Analysis of the United Net‐ work for Organ Sharing (UNOS) registry between 1991 to 1997 demonstrated an 11% reduc‐ tion in 3-year graft survival rate (p<0.001) between transplants involving 6 compared to 0 HLAmismatches, with the most discernible difference in survival was observed between recipients with 0 to 1 HLA-mismatch [55]. In the UNOS study, the association between HLA-mismatches andreducedgraft survivalappearedtobe relatedtomismatchesattheHLA-DRlocuswithinthe firstyearpost-transplant,whereasmismatchesattheHLA-ABlociweremoreimportantbeyond the first year post-transplant. However, the association between HLA-mismatches and graft survival in the era of modern immunosuppression remains contradictory [56]. Analysis of the CTSdatademonstratedthattheimportanceofHLA-matchingongraftoutcomesremainedstrong during the two decades of 1985-1994 and 1995-2004, suggesting that association between HLAmismatches and graft survival remains robust in the era of modern immunosuppression [47]. Unlike the other large registry studies that had focused on deceased donor renal transplants, the study by *Lim WH et al* using ANZDATA registry data evaluated both live and deceased donor renal transplants. Similarly, the authors demonstrated a strong association between HLAmismatchesandoverallgraft survivalforbothliveanddeceaseddonorrenaltransplants (Figure 3B),especiallybetweenthosereceiving0-HLA-mismatchedkidneyscomparedtothosereceiving ≥1 HLA-mismatched kidneys [46]. In contrast, analysis of the UNOS data suggested that the relative importance of HLA-mismatches and reduced graft survival may have diminished in recent years, whereas other factors such as donor age retained their statistical significance over timepromptingthesuggestionthatkidneyallocationalgorithmsbasedpredominantlyonHLAmatching should be modified [57]. However, this study focused on era between 1994 and 1998

**Figure 3.** (a) Odds ratio plot of HLA mismatches and acute rejection according to donor type (reference live donor 0 HLA mismatch) and corresponding table of the adjusted odds ratio between HLA mismatches and acute rejection ac‐ cording to donor type (reference live or deceased donor 0 HLA mismatch; adapted from *Lim WH et al* Clin Transplant 2012) [46]. (b) Kaplan–Meier survival curve of overall graft failure according to the number of HLA mismatches with corresponding numerical table of the number at risk at 0, 4 and 8 years post-transplant (adapted from *Lim WH et al* Clin Transplant 2012) [46].

The association between acute rejection and graft survival appears well established. In the study by *Wissing et al*, the authors had shown rejection within the first year post-transplant was independently associated with a significant reduction in overall (57% vs 83%; p=0.0004) and death-censored graft survival (63.5% vs 91.2%; p<0.0001) [51], a finding corroborated by ANZDATA registry analysis [46].

Although HLA-DR mismatches appear to be of greater importance in predicting graft outcomes compared to HLA-AB mismatches, the current kidney allocation algorithm in Australia specifically favours fully HLA-DR matched recipients but still takes into account HLA-AB matching, therefore confers an appropriate concession to allow satisfactory HLAmatching but avoiding discrimination to potential recipients with rare HLA combinations as HLA-DR locus has fewer polymorphisms compared to HLA-AB loci [58]. Previous studies have demonstrated that allocation based predominantly on HLA-DR matching, as imple‐ mented in the United States, may eliminate any advantage of HLA-AB matching but this remains controversial [59, 60]. Analysis of Scientific Registry of Transplant Recipients (SRTR) of 108,701 deceased donor renal transplant recipients demonstrated that the elimination of allocation priority for HLA-B mismatches improved the transplant potential of ethnic minor‐ ities and this policy had achieved comparable renal allograft survival compared to historical graft outcomes prior to the change in allocation policy [61]. Although the presence of HLA- Cw, DP and DQ DSA have been shown to be associated with poorer graft outcomes [62, 63], matching at the HLA-Cw, DP and DQ loci are not routinely performed and therefore is not explicitly included in the allocation of deceased donor kidneys in any countries.
