Autoantibodies to LG3 are associated with poor long-term survival after liver retransplantation.

Autoantibodies are detrimental to the survival of organ transplantation. We demonstrated that Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) were associated with poor outcomes after liver retransplantation. To examine the effect of other autoantibodies, we studied a retrospective cohort of 93 patients who received a second liver transplant. Pre-retransplant sera were tested with Luminex-based solid-phase assays. Among 33 tested autoantibodies, 15 were significantly higher in 48 patients who lost their regrafts than 45 patients whose regrafts were still functioning. Specifically, patients with autoantibodies to the C-terminal laminin-like globular domain of Perlecan (LG3) experienced significantly worse regraft survival (p = .002) than those with negative LG3 autoantibodies (LG3-A). In multivariate analysis, LG3-A (HR = 2.35 [1.11-4.98], p = .027) and AT1R-AA (HR = 2.09 [1.07-4.10], p = .032) remained significant predictors of regraft loss after adjusting for recipient age and sex. There were synergistic deleterious effects on regraft survival in patients who were double-positive for LG3-A and donor-specific antibody (DSA) (HR = 5.26 [2.15-12.88], p = .001), or LG3-A and AT1R-AA (HR = 3.23 [1.37-7.66], p = .008). All six double-positive patients lost their liver regrafts. In conclusion, LG3-A is associated with inferior long-term outcomes of a second liver transplant. Screening anti-HLA antibodies and autoantibodies such as LG3-A/AT1R-AA identifies patients with a higher risk for liver transplantation.

Angiotensin II type I receptor agonistic autoantibodies are associated with poor allograft survival in liver retransplantation.

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 = .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 >17 U/mL before the second liver transplantation. In 22 (23.4%) patients, strong positive AT1R-AA (defined as >40 U/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 AT1R-AA <40 U/mL (P = .035). In multivariate Cox models that included confounders such as sex and age, either AT1R-AA >40 U/mL (HR = 1.999 [1.085-3.682], P = .026) or increased concentrations of AT1R-AA (HR = 1.003 [1.001-1.006] per incremental U/mL, P = .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.

The impact of alloantibodies directed against the second donor on long-term outcomes of repeat liver transplantation.

BACKGROUND: Despite reports that associate donor specific antibody (DSA) with rejection after liver transplantation, grafts are still allocated according to blood group (ABO) but not human leukocyte antigen (HLA) compatibility, possibly due to the absence of an easily discernible clinical association between adverse recipient outcome and DSA. Re-transplantation provides a test environment where the presence of preformed DSA is prevalent and its effect on outcome should be apparent. METHODS: All patients undergoing a second liver transplantation with available pre-operative serum were included with the exception of ABO incompatible or multiple organ transplants. Banked sera were tested for anti-HLA antibodies with Luminex-based solid phase assays. Anti-HLA antibodies to the second donor (D2SA) were determined using antibodies specificity and HLA typing of 2nd liver donor. RESULTS: Preformed HLA antibodies directed to second liver transplantation (D2SA) were found in 31 (39%) of the 79 patients that were included in the study. Primary and re-transplantation characteristics were similar in both subgroups except first graft survival which was significantly shorter in recipients who are negative for D2SA. Mean survival of the second graft was similar in D2SA+ and D2SA- cohorts [8.55 (range, 0.01-24.74) vs. 7.56 (range, 0-23.53) years respectively, P=0.574]. Mean patient survival after 2nd liver transplantation was similar in D2SA+ and D2SA- cohorts [9.11 (range, 0.01-24.74) vs. 8.10 (range, 0-23.53) years respectively, P=0.504]. Subgroup univariate analysis demonstrated no detrimental effect of class, locus, or strength of D2SA on survival of the second liver transplant. In multivariate cox regression model, neither class I D2DSA (HR =1.101, P=0.92) nor class II D2SA (HR =1.74, P=0.359) were significant risks of graft failure. CONCLUSIONS: Presence of D2SA was not found to be associated with inferior outcomes in this retrospective cohort study of liver re-transplantation suggesting that changes to the allocation system are not required.

Patients with immunological diseases or on peritoneal dialysis are prone to false positive flow cytometry crossmatch.

Despite implementation of virtual crossmatches, flow cytometry crossmatches (FCXM) are still used by many transplant centers to determine immunological risk before kidney transplantation. To determine if common profiles of patients prone to false positive FCXM exist, we examined the demographics and native diseases of kidney patients tested with autologous FCXM (n = 480). Improvements to FCXM and cell isolation methods significantly reduced the positive rate from 15.1% to 5.3%. Patients with native diseases considered 'immunological' (vasculitis, lupus, IgA nephropathy) had more positive autologous FCXM (OR = 3.36, p = 0.003) vs. patients with all other diseases. Patients who were tested using our updated method (n = 321) still showed that these immunological diseases were a significant predictor for positive autologous FCXM (OR = 4.79, p = 0.006). Interestingly, patients on peritoneal dialysis (PD) also had significantly more positive autologous FCXM than patients on hemodialysis or waiting for pre-emptive kidney transplants (OR = 3.27, p = 0.02). These findings were confirmed in patients who had false positive allogeneic FCXM. Twenty of 24 (83.3%) patients with false positive allogeneic FCXM tested with updated method either had immunological diseases originally or were on PD. Our findings are helpful when interpreting an unexpected positive FCXM, especially for transplantation from deceased donors.