The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre-and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

Preformed donor-specific human leukocyte antigen antibodies (DSAs) are considered a contraindication to the transplantation of most solid organs other than the liver. Conflicting data currently exist on the importance of preformed DSAs in rejection and patient survival after liver transplantation (LT). To evaluate preformed DSAs in LT, we retrospectively analyzed prospectively collected samples from all adult recipients of primary LT without another organ from January 1, 2000 to May 31, 2009 with a pre-LT sample available (95.8% of the patients). Fourteen percent of the patients had preformed class I and/or II DSAs with a mean fluorescence intensity (MFI) 5000. Preformed class I DSAs with an MFI 5000 remained persistent in only 5% of patients and were not associated with rejection. Preformed class II DSAs with an MFI of 5000 to 10,000 remained persistent in 23% of patients, and this rate increased to 33% for patients whose MFI was 10,000 (P < 0.001). Preformed class II DSAs in multivariable Cox proportional hazards modeling were associated with an increased risk of early rejection [hazard ratio (HR) 5 1.58; p = 0.004]. In addition, multivariate modeling showed that in comparison with no DSAs (MFI < 1000), preformed class I and/or II DSAs with an MFI 5000 were independently correlated with the risk of death (HR 5 1.51; p = 0.02). The role of donor-specific human leukocyte antigen antibodies (DSAs) in liver transplantation (LT) has long been debated. [1][2][3][4][5] Early analyses revealed the liver's ability to absorb preformed DSAs; some were absorbed without consequence, and others resulted in preservation injury and/or vanishing bile duct syndrome. [4][5][6][7][8] Early clinical data based on cytotoxic crossmatching were united in leading to the conclusion of an absence of hyperacute rejection (with rare exception), but they were divided with respect to conclusions about short-term and longer term outcomes. 1,9,10 However, in the 1980s, graft failure rates were high and limited the analysis of long-term outcomes. Stratification by crossmatch strength in the early 1990s first elucidated increased 1-month graft failure rates in crossmatch-positive patients (29%) versus low-level crossmatch-positive and crossmatchnegative patients (16%). 2,3,9 In fact, "rejection was the most common cause of primary liver allograft failure" in patients with a positive crossmatch. 2 Recent technological improvements have resulted in mounting evidence that antibody-mediated rejection occurs in LT patients; single-antigen bead analyses have found correlations between preformed DSAs and Additional Supporting Information may be found in the online version of this article.Abbreviations: AIH, autoimmune hepatitis; CNI, calcineurin inhibitor; DSA, donor-specific human leukocyte antigen antibody; HLA, human leukocyte antigen; HR, hazard ratio; IgG, immunoglobulin G; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MFI, mean fluorescence intensity; NASH, nonalcoholic steatohepatitis; NS, not significant; PBC, primary bil...

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The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

Donor‐specific alloantibodies (DSA) can cause acute antibody‐mediated rejection (AMR) in all solid organ allografts. However, long‐term outcome in patients with posttransplant DSA needs further study. We retrospectively evaluated prospectively collected paired serum, tissue, and data on 45 matched DSA− positive [DSA+; mean florescence intensity (MFI) ≥10 000] and ‐negative (DSA−) recipients of a primary liver‐only allograft from January 2000 to April 2009. Blinded histopathologic evaluation demonstrated that DSA+ versus DSA− patients were more likely to have subtle inflammation and unique patterns of fibrosis, despite normal or near‐normal liver function tests. Stepwise multivariable modeling developed a score (putatively named the chronic AMR [cAMR] score) that included interface activity, lobular inflammation, portal tract collagenization, portal venopathy, sinusoidal fibrosis, and hepatitis C virus status. The score was developed (c = 0.811) and cross‐validated (c = 0.704) to predict allograft failure. Two cutoffs were employed to optimize sensitivity and specificity (80% each); a value >27.5 predicted 50% 10‐year allograft failure. We propose chronic AMR as a potential new entity defined by (1) a high cAMR score, (2) DSA, and (3) elimination of other potential causes of a similar injury pattern. In conclusion, cAMR score calculation identified liver allograft recipients with DSA at highest risk for allograft loss, although independent validation is needed.