Introduction. With modern immunosuppression it is believed that HLA mismatch (mm) have little impact on kidney graft survival, except for the benefits of 0 HLA mm and detriment of HLA II mm. These conclusions are based on studies done before we fully appreciated the importance of donor specific antibodies (DSA). We examined the relationship between HLA mm and graft survival in DSA negative recipients.

Methods. Included are 764 DSA negative adult kidney recipients, transplanted between 2000& 2010; age 53±13 years; 78% living donors; f/u 74±35 months. 83% received thymoglobulin induction and 91% triple immunosuppression with tacrolimus. Study end point was death-censored graft loss (GL).

Results. 13% of recipients had 0 HLA mm. Increasing HLA mm related to a higher GL [HR=1.25 (1.08-1.44), p=0.002] independently of recipient or donor age, acute rejection (AR), BK, graft function and proteinuria at one year. Surprisingly, this relationship was due to HLA I mm (GL vs A mm, HR=1.61, p=0.02; B mm, HR=1.80, p=0.009) while HLA II mm did not relate to GL (GL vs DR mm, p=0.53; DQ mm, p=0.57). For example, 5/10 year GL for B mm=0, 1 or 2 were: 2.6/7.3%, 3.1/17.5% and 6.0/27.7%, respectively. Increasing A&B mm related to risk of AR during the first 2 years (HR=1.53, p=0.003) particularly AR type 1. In contrast, HLA II mm did not relate to risk of AR. Increasing A&B mm also increased the risk of developing new DSA, particularly class II. In B mm=0, 1 or 2 recipients new DSA II_1year were 1.6% (N=160), 11.2% (N=343) and 21.4% (N=261) respectively (p<0.0001). Development of new DSA II_1year related to A mm (Logistic regression, OR=2.49, p<0.0001), B mm (OR=2.94, p<0.0001) and DR mm (OR=2.99, p<0.0001). Increasing A&B mm increased the risk of alloimmune GL, i.e. GL due to AR or due to chronic antibody rejection. Thus, in A mm=0, 1 or 2, 5/10 year alloimmune GL were 0/4.6%, 1.7/7.7% and 3.1/13.4%, respectively (p=0.016).

Summary and conclusions. In DSA negative recipients, A&B mm relate to higher risk of AR, new DSA II and immunologic GL. DR & DQ mm did not relate to GL but related to formation of new DSA II. These results suggest that avoiding A&B mm in un-sensitized recipients will minimize acute rejection, avoid sensitization against HLA class II and ultimately reduce immunologic graft losses.

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