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Angiotensin II type I receptor (AT1R) agonistic autoantibodies (AT1R-AA) are detrimental to kidney transplantation. Early studies suggested a similar negative effect in primary liver transplantation. Here, we studied AT1R-AA in a retrospective cohort of 94 patients who received a second liver transplant to determine their prevalence and effects. The concentrations of preformed AT1R-AA before transplantation were higher (p=0.019) in the 48 patients who lost their liver grafts than in the 46 patients whose grafts survived. About half (48/94, 51.1%) of the patients were positive for AT1R-AA>17U/ml before the second liver transplantation. In 22 (23.4%) patients, strong positive AT1R-AA (defined as >40U/ml) were detected, of whom 16 (72.7%) patients lost their grafts. Based on Kaplan-Meier analysis, patients with strong positive AT1R-AA had significantly worse graft survival than those with Accepted Article This article is protected by copyright. All rights reserved. AT1R-AA<40U/ml (p=0.035). In multivariate Cox models that included confounders such as sex and age, either AT1R-AA>40U/ml [HR=1.999 (1.085-3.682), p=0.026] or increased concentrations of AT1R-AA [HR=1.003 (1.001-1.006) per incremental U/ml, p=0.019] were significantly associated with elevated risk for graft loss. In conclusion, our data indicate that there is a high prevalence of AT1R-AA in candidates for second liver transplantation and that their presence is associated with inferior long-term outcomes of the second graft.

Both alloimmune and autoimmunity contribute to graft loss in organ transplantation. The detrimental roles of donor-specific antibodies (DSA) to human leukocyte antigen (HLA) are well-established in transplantation of kidney, pancreas, heart, lung, and intestine, 1-3 but less so in liver transplantation (LT). [4][5][6][7][8][9][10][11] Antibodies to non-HLA antigens, such as autoantibodies or natural polyclonal antibodies, were also described in recipients of solid organs 12 and allogeneic hematopoietic stem cells. 13 Autoantibodies, which may be generated through the exposure of cryptic antigens, are detrimental for the survival of the kidney, [14][15][16] lung, 17 heart, 18,19 liver, [20][21][22] and intestinal 23 allografts. The prevalence of antibodies to HLA and autoantigens are often higher before retransplantation than before the first transplantation, especially in recipients of kidney grafts. 24 Recipients of redo liver transplant usually have worse outcomes in comparison with recipients of first-time liver

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