Chronic Active Rejection Research Articles

Face transplantation: A longitudinal histological study focusing on chronic active and mucosal rejection in a series with long-term follow-up

The 2007 Banff working classification of skin-containing Tissue Allograft Pathology addressed only acute T cell-mediated rejection in skin. We report the longitudinal long-term histological follow-up of six face transplant recipients, focusing on chronic and mucosal rejection. We identified three patterns suggestive of chronic rejection (lichen planus-like, vitiligo-like and scleroderma-like). Four patients presented lichen planus-like and vitiligo-like chronic rejection at 52±17months posttransplant with severe concomitant acute T cell-mediated rejection. After lichen planus-like rejection, two patients developed scleroderma-like alterations. Graft vasculopathy with C4d deposits and de novo DSA led to subsequent graft loss in one patient. Chronic active rejection was frequent and similar patterns were noted in mucosae. Concordance between 124 paired skin and mucosal biopsies acute rejection grades was low (κ=0.2, p=.005) but most grade 0/I mucosal rejections were associated with grade 0/I skin rejections. We defined discordant (grade≥II mucosal rejection and grade 0/I skin rejection) (n=55 [70%]) and concordant (grade≥II rejection in both biopsies) groups. Mucosal biopsies of the discordant group displayed lower intra-epithelial GranzymeB/FoxP3 ratios suggesting a less aggressive phenotype (p=.08). The grading system for acute rejection in mucosa may require phenotyping. Whether discordant infiltrates reflect a latent allo-immune reaction leading to chronic rejection remains an open question.

1 -YEAR PROTOCOL BIOPSIES IN PEDIATRIC KIDNEY TRANSPLANT CHILDREN: ARE UNFAVORABLE HISTOLOGICAL LESIONS RELATED TO NO ADHERENCE?

Introduction: In adult recipients histological findings in surveillance biopsies at 1-year post kidney transplantation (KT) correlate independently with short and long-term graft survival. Donor specific antibodies (dnDSA) are associated with antibody- mediated rejection. Non-adherence (NOA) to treatment, is a risk factor for dnDSA. Studies in children with KT with protocol biopsies are scarce. Objective: To evaluate the prevalence of favorable (FAV) and unfavorable (UNFAV) histological lesions (FAV) for graft survival in 1-year protocol biopsies of KT children and to identify risk variables for these lesions. Methods: Prospective cohort study in all recipients of a 1st KT between 06/01/2018 and 05/30/2019. (TABLE 1) According to their histological risk, lesions were grouped in “FAV” and “UNFAV”. “FAV” lesions were: 1) minor morphological changes, with absence of inflammation and / or fibrosis and / or chronic glomerulopathy or glomerulonephritis, 2) Acute Interstitial inflammation without interstitial fibrosis or glomerular changes 3) Mild Interstitial fibrosis with absence of interstitial inflammation. “UNFAV” lesions were: 1) moderate-severe interstitial fibrosis without inflammation 2) acute or chronic active rejection mediated by antibodies or T cells 3) de novo glomerular disease 4) polyoma virus-associated nephropathy. dn-DSA were sought simultaneously with kidney biopsy. TAC and / or SRL variation coefficient (VC) >25% was considered a surrogate of NOA. Results: 38 children were included. 29 had “FAV” lesions (76%): 23, Minimal morphological changes, and 6 mild fibrosis. Nine had “UNFAV” histology (24%): One had disease recurrence, three acute vascular rejection, (2/3 subclinical rejection; 1/3 DSA+) and four had moderate fibrosis (2 had graft hydronephrosis and 2 had previous AR,1DSA+). Mean eGFR in patients with “UNFAV” lesions was 39 ± 12.1 ml / min/ 1.73m2 vs 65.3 ± 18 ml / min / 1.73m2 in those with “FAV” (p=0.0003). Both groups had similar pre KT clinical and demographic characteristics. (TABLE2). UNFAV patients had higher incidence of previous Acute Rejection (TABLE2). TAC or SRL VC was: < 25% in 71% of patients (n= 27), and > 25% in 19% of patients (n=11), those with irregular intake. Children with VC> 25% had higher risk of an “UNFAV” lesion in protocol biopsy (OR: 4.8; p=0,04) and higher prevalence of dnDSA (18% vs 0%; p=0.02) Conclusion: In this cohort, FAV lesions were the most prevalent and were associated with negative dnDSA and TAC or SRL VC <25%. Children with UNFAV lesions had lower eGFR. Those with TAC or SRL VC>25% had higher risk of an “UNFAV” lesion, and higher prevalence of dnDSA. Follow-up of this cohort is imperative.

Clinical Management of Kidney Allograft Dysfunction

Allograft dysfunction is a common problem after kidney transplant. Allograft rejection is an important entity, and timely diagnosis and appropriate treatment are essential for caring transplant recipients. Hyperacute rejection is mediated by the preformed donor specific antibody, while accelerated acute rejection represents an anamnestic response by memory B and T cells. They occur early after transplant. Acute cellular rejection is relatively common and usually responds to pulse corticosteroids or antithymocyte globulin (ATG). The complexity of antibody-mediated rejection (AMR) as well as its detrimental effect has been increasingly recognized. The treatment of acute AMR requires a combination of several modalities, such as plasmapheresis or immunoadsorption, IVIG, corticosteroids, rituximab and ATG. After treatment of rejection episode, the maintenance immunosuppressive drugs should be adjusted to prevent further acute rejection and/or evolution into chronic active rejection. Chronic rejection is not reversible and it has been recognized as the most important cause of chronic graft dysfunction and failure.

Prevention and treatment of alloantibody-mediated kidney transplant rejection

Antibody-mediated rejection (AMR), which is commonly caused by preformed and/or de novo HLA alloantibodies, has evolved as a leading cause of early and late kidney allograft injury. In recent years, effective treatment strategies have been established to counteract the deleterious effects of humoral alloreactivity. One major therapeutic challenge is the barrier of a positive pretransplant lymphocytotoxic crossmatch. Several apheresis- and/or IVIG-based protocols have been shown to enable successful crossmatch conversion, including a strategy of peritransplant immunoadsorption for rapid crossmatch conversion immediately before deceased donor transplantation. While such protocols may increase transplant rates and allow for acceptable graft survival, at least in the short-term, it has become evident that, despite intense treatment, many patients still experience clinical or subclinical AMR. This reinforces the need for innovative strategies, such as complementary allocation programs to improve transplant outcomes. For acute AMR, various studies have suggested efficiency of plasmapheresis- or immunoadsorption-based protocols. There is, however, no established treatment for chronic AMR and the development of strategies to reverse or at least halt chronic active rejection remains a big challenge. Major improvements can be expected from studies evaluating innovative therapeutic concepts, such as proteasome inhibition or complement blocking agents.

Ultrastructural analysis of the Fisher to Lewis rat model of chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the leading cause of graft loss following kidney transplantation. One factor contributing to CAN is chronic alloimmune injury. However, the involvement of alloantigen-dependent and -independent factors in CAN is unclear. The pathomechanism of CAN has been extensively studied by utilizing the Fischer-to-Lewis (F344-to-LEW) rat model. Transplant capillaropathy (circumferential multiplication of the peritubular capillary basement membrane) and transplant glomerulopathy (reduplication of the glomerular basement membrane) have recently been validated clinicopathologically as ultrastructural indicators of chronic alloimmune injury. To investigate the presence of these markers, F344-to-LEW kidneys were examined by electron and light microscopy 32, 40 and 52 weeks after implantation. F344 rats with or without 30-min ischemia of the left kidney following right nephrectomy served as controls. All transplanted rats displayed marked proteinuria. On electron microscopy, transplant capillaropathy, transplant glomerulopathy, and T-cell cytotoxicity (indicator of ongoing cellular rejection) were absent. On light microscopy, the arteries were devoid of intimal fibrosis. Focal-segmental glomerulopathy resembling hyperfiltration injury was encountered, with mild interstitial infiltration, fibrosis, and tubular atrophy. The proteinuria and kidney pathology were more severe in transplanted than in ischemic or uninephrectomized rats. Because chronic-active rejection could not be detected between weeks 32 and 52, we propose that the alloantigen-dependent initial graft injury subsides, but induces the late events: glomerular hyperfiltration, proteinuria, and glomerulosclerosis. Accordingly, the model - in the late phase - is suitable to investigate alloantigen-independent factors of CAN and lacks markers of alloantigen-dependent processes.

Monotherapy with the novel human anti-CD154 monoclonal antibody ABI793 in rhesus monkey renal transplantation model.

This study assesses the safety and efficacy of the novel human anti-human CD154 monoclonal antibody ABI793 in rhesus monkeys. Outbred rhesus monkeys were used for renal transplantation from major histocompatibility complex-mismatched donors. Seven recipients were treated with ABI793, and six untreated recipients were used as controls. Graft function was monitored by urine output, serum creatinine, and renal biopsy. Phenotypic analysis of peripheral blood lymphocytes and mixed lymphocyte reaction were performed before transplantation and periodically after transplantation. Anti-donor major histocompatibility complex class I antibody levels were measured at the time of sacrifice. Monkeys in the treated group demonstrated prolonged graft survival compared with controls. One monkey was sacrificed because of a urine leak on postoperative day 13. Three monkeys were sacrificed because of acute rejection (days 44, 149, and 158). Two monkeys were sacrificed because of chronic active rejection (days 154 and 221). One monkey was sacrificed on day 139 without rejection to observe the effects of ABI793 in the absence of rejection. There were no obvious clinical side effects of ABI793, but microscopic thromboembolic changes were observed in two monkeys. Lymphocyte subsets remained unaltered in all monkeys. Mixed lymphocyte reaction showed nonspecific suppression 6 weeks after transplantation. The monkeys with chronic active rejection showed relatively strong alloantibody responses. ABI793 induces prolonged renal allograft survival in rhesus monkeys. Nevertheless, thromboembolic complications may occur and chronic allograft nephropathy may develop after anti-CD154 treatment is discontinued.