Nonvascularized human skin chronic allograft rejection.

A 65-year-old man had extensive burns of the lower legs in 1991, at the age of 40 years. He was treated by nonvascularized and de-epithelialized, allogeneic split-thickness skin allograft and cyclosporine monotherapy for 2 months. Ulcers developed between 10 and 25 years after transplantation and a surgical debridement on the lower extremities was required. Analyses of the removed tissue allografts showed chronic antibody-mediated and cellular rejection with extensive and dense fibrosis, and diffuse capillary C4d deposits. An anti-DRB1*08:01, donor-specific antibody was present. A unique clinical condition with late immunopathological features of human skin chronic allograft rejection is reported

Safety and efficacy of eculizumab in the prevention of antibody-mediated rejection in living-donor kidney transplant recipients requiring desensitization therapy: A randomized trial

We report results of a phase 2, randomized, multicenter, open‐label, two‐arm study evaluating the safety and efficacy of eculizumab in preventing acute antibody‐ mediated rejection (AMR) in sensitized recipients of living‐donor kidney transplants requiring pretransplant desensitization (NCT01399593). In total, 102 patients under‐ went desensitization. Posttransplant, 51 patients received standard of care (SOC) and 51 received eculizumab. The primary end point was week 9 posttransplant treat‐ ment failure rate, a composite of: biopsy‐proven acute AMR (Banff 2007 grade II or III; assessed by blinded central pathology); graft loss; death; or loss to follow‐up. Eculizumab was well tolerated with no new safety concerns. No significant difference in treatment failure rate was observed between eculizumab (9.8%) and SOC (13.7%; P = .760). To determine whether data assessment assumptions affected study out‐ come, biopsies were reanalyzed by central pathologists using clinical information. The resulting treatment failure rates were 11.8% and 21.6% for the eculizumab and SOC groups, respectively (nominal P = .288). When reassessment included grade I AMR, the treatment failure rates were 11.8% (eculizumab) and 29.4% (SOC; nominal P = .048). This finding suggests a potential benefit for eculizumab compared with SOC in preventing acute AMR in recipients sensitized to their living‐donor kidney transplants (EudraCT 2010‐019630‐28)

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody-mediated rejection

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell–mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation

Overlapping Pathways to Transplant Glomerulopathy: Chronic Humoral Rejection, Hepatitis C Infection and Thrombotic Microangiopathy

Background:Transplant glomerulopathy (TG) has received much attention in recent years as a manifestation of chronic humoral rejection (CHR). However, many cases lack C4d deposition and/or circulating donor-specifi c antibodies, and the contribution of other potential causes has not been fully addressed.Methods: Of 209 consecutive renal allograft indication biopsies performed for chronic allograft dysfunction, 25 that met pathologic criteria of TG (>10% duplication of the GBM without immune complex deposition) were examined for various etiologies, including hepatitis C infection (HCV), thrombotic microangiopathy (TMA), and CHR. 29 cases of biopsy-proven isolated chronic calcineurin inhibitor toxicity from the same time period were used as controls for comparing the prevalence of HCV.Results: Three partially overlapping categories accounted for 84% of the cases: C4d+TG (48%), HCV+TG (36%) and TMA+TG (32%). The majority of TMA+ cases were HCV+ (63%) and the majority of HCV+ cases had TMA (56%). Donor specifi c antibodies were associated with C4d+TG (7/8 vs. 1/4 C4d-TG; P<0.02), but not with HCV+TG. The prevalence of HCV was higher in the TG group than in 29 control patients without TG (36% vs. 7%, P<0.01). HCV+TG patients developed allograft failure earlier than HCV-TG patients (67.2 ± 60.2 mo versus 153.4 ± 126.2 mo, P=0.02). On a multivariate analysis, out of HCV, TG and C4d, only HCV was found to be a signifi cant risk factor for a more rapid allograft loss.Conclusion: We conclude that TG is not a specifi c diagnosis, but a pattern of pathologic injury with 3 major overlapping pathways involving CHR, HCV infection and TMA. It is important to distinguish these mechanisms, as they may have differentprognostic and therapeutic implications

Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy.

Transplant glomerulopathy (TG) has received much attention in recent years as a symptom of chronic humoral rejection; however, many cases lack C4d deposition and/or circulating donor-specific antibodies (DSAs). To determine the contribution of other causes, we studied 209 consecutive renal allograft indication biopsies for chronic allograft dysfunction, of which 25 met the pathological criteria of TG. Three partially overlapping etiologies accounted for 21 (84%) cases: C4d-positive (48%), hepatitis C-positive (36%), and thrombotic microangiopathy (TMA)-positive (32%) TG. The majority of patients with confirmed TMA were also hepatitis C positive, and the majority of hepatitis C-positive patients had TMA. DSAs were significantly associated with C4d-positive but not with hepatitis C-positive TG. The prevalence of hepatitis C was significantly higher in the TG group than in 29 control patients. Within the TG cohort, those who were hepatitis C-positive developed allograft failure significantly earlier than hepatitis C-negative patients. Thus, TG is not a specific diagnosis but a pattern of pathological injury involving three major overlapping pathways. It is important to distinguish these mechanisms, as they may have different prognostic and therapeutic implications

Timed Simulation of Extended AADL-Based Architecture Specifications with Timed Abstract State Machines

The Architecture Analysis and Design Language (AADL) is a popular language for architectural modeling and analysis of software intensive systems in application domains such as automotive, avionics, railway and medical systems. These systems often have stringent real-time requirements. This paper presents an extension to AADL's behavior model using time annotations in order to improve the evaluation of timing properties in AADL. The translational semantics of this extension is based on mappings to the Timed Abstract State Machines (TASM) language. As a result, timing analysis with timed simulation or timed model checking is possible. The translation is supported by art Eclipse-based plug-in and the approach is validated with a case study of an industrial production cell system