Faculty Bibliography

Background/UNASSIGNED:Donor-specific antibodies (DSA) to human leukocyte antigen increase the risk of accelerated rejection and allograft damage and reduce the likelihood of successful transplantation. Patients with full-thickness facial burns may benefit from facial allotransplantation. However, they are at a high risk of developing DSA due to standard features of their acute care. Case Presentation/UNASSIGNED:A 41-year-old male with severe disfigurement from facial burns consented to facial allotransplantation in 2014; panel reactive antibody score was 0%. In August of 2015, a suitable donor was found. Complement-dependent cytotoxicity crossmatch was negative; flow cytometry crossmatch was positive to donor B cells. An induction immunosuppression strategy consisting of rabbit antithymocyte globulin, rituximab, tacrolimus, mycophenolate mofetil (MMF), and methylprednisolone taper was designed. Total face, scalp, eyelid, ears, and skeletal subunit allotransplantation was performed without operative, immunological, or infectious complications. Maintenance immunosuppression consists of tacrolimus, MMF, and prednisone. As of posttransplant month 24, the patient has not developed acute rejection or metabolic or infectious complications. Conclusions/UNASSIGNED:To our knowledge, this is the first report of targeted B cell agents used for induction immunosuppression in skin-containing vascularized composite tissue allotransplantation. A cautious approach is warranted, but early results are promising for reconstructive transplant candidates given the exceptionally high rate of acute rejection episodes, particularly in the first year, in this patient population.

Background: Inheritance of two APOL1 risk variants accounts for the excess risk of non-diabetic ESRD in African Americans when compared to Caucasian, Hispanic and Asian Americans. African American living donors have a higher risk of ESRD than matched non-black donors. APOL1 genotyping in potential kidney donors of African descent may identify individuals at risk for progressive CKD following donation.
Method(s): We report the retrospective analysis of APOL1 genotyping in a cohort of African American potential kidney donors. In July 2016, we initiated targeted genotyping of all African American kidney donor candidates. African American candidates with two APOL1 risk variants were excluded from kidney donation.
Result(s): A total of 28 African American kidney donor candidates were evaluated between July 2016 and April 2018. 2 (7%) were found to have two APOL1 risk variants (high risk genotype). Low risk genotype was identified in 10 (36%) candidates who had one risk variant and 16 (57%) candidates who had none. To date, 15 candidates have completed their donor work-up. Of these, 7 (47%) have already undergone donor nephrectomy, and 4 (27%) were cleared for surgery and are awaiting operation. 4 (27%) of the candidates did not meet our center specific criteria for donation. 2 out these 4 candidates who were excluded from donation were ruled out expressly for having been found to have two APOL1 risk variants.
Conclusion(s): APOL1 genotyping led to the exclusion of two donors who might have previously been allowed to donate, possibly mitigating their risk of CKD/ESRD and suboptimal graft outcomes in recipients. (Table Presented)

The non-life-saving nature of facial transplantation (FT) has raised concerns over the procurement of a facial allograft (FA) and allocated solid organs (SO) from a single donor. In response, FT teams have described their experiences performing simultaneous and asynchronous procurement. One unanimous conclusion is that the safe procurement of life-saving organs must be given priority during the donor operation

Con A hepatitis is regarded as a T cell-mediated model of acute liver injury. Mincle is a C-type lectin receptor that is critical in the immune response to mycobacteria and fungi but does not have a well-defined role in preclinical models of non-pathogen-mediated inflammation. Because Mincle can ligate the cell death ligand SAP130, we postulated that Mincle signaling drives intrahepatic inflammation and liver injury in Con A hepatitis. Acute liver injury was assessed in the murine Con A hepatitis model using C57BL/6, Mincle-/-, and Dectin-1-/- mice. The role of C/EBPbeta and hypoxia-inducible factor-1alpha (HIF-1alpha) signaling was assessed using selective inhibitors. We found that Mincle was highly expressed in hepatic innate inflammatory cells and endothelial cells in both mice and humans. Furthermore, sterile Mincle ligands and Mincle signaling intermediates were increased in the murine liver in Con A hepatitis. Most significantly, Mincle deletion or blockade protected against Con A hepatitis, whereas Mincle ligation exacerbated disease. Bone marrow chimeric and adoptive transfer experiments suggested that Mincle signaling in infiltrating myeloid cells dictates disease phenotype. Conversely, signaling via other C-type lectin receptors did not alter disease course. Mechanistically, we found that Mincle blockade decreased the NF-kappabeta-related signaling intermediates C/EBPbeta and HIF-1alpha, both of which are necessary in macrophage-mediated inflammatory responses. Accordingly, Mincle deletion lowered production of nitrites in Con A hepatitis and inhibition of both C/EBPbeta and HIF-1alpha reduced the severity of liver disease. Our work implicates a novel innate immune driver of Con A hepatitis and, more broadly, suggests a potential role for Mincle in diseases governed by sterile inflammation.

Purpose: There is a significant variation in the MELD scores and subsequent morbidity among liver recipients in the US. Larger OPOs consistently serve patients with advanced disease. Previous studies have shown 2.5 times greater prevalence of transplanted patients with MELD ³ 24 in these OPOs. CMS recent reimbursement adjustments may disproportionately affect certain programs given their increased prevalence of patients with more advanced disease. Methods: We analyzed the prevalence of transplants among patients with high UNET MELD scores and associated charges, costs, and reimbursements. We compared low, medium and high MELD score groups. Between 2014-2015, 43 liver transplants, all with >30 days survival, were analyzed. Results: Only 2 had MELD scores below 25 at transplant, both of which from live donors. 95% of patients had MELD scores above 25 and among these, 18% had MELD 40 or were Status 1. Compared to the national average, our MELD scores were: 25% 21-30 (National 21.5%, p >0.05), 70.5% 31-40 (National 25.9%, p < 0.001), and 4.5% Status 1 (National 5.9%, p >0.05). For MELD scores 21-30, hospital charges averaged $645,214 and reimbursements were $150,706. For MELD scores 31-39, charges were $686,720, and reimbursement were $139,776. Reviewing MELD 40/ Status 1 patients, the average hospital charges and reimbursements were $1,136,813 and $293,776 respectively. We compared their amounts to the MELD 40 patients who had hospital charges of $625,371 and reimbursements of $142,051 respectively. This demonstrated a loss of $843,037 for the first group and $483,320 for the second. Length of stay was 32 days for MELD 40/ Status 1 and 8 days for MELD 40 (p < 0.000). Conclusion: ³ 40 MELD patients have a huge financial impact on institutions. The difference between 25-39 and ³40 MELD points is greater than half a million dollars. These data reflect and include dialysis, intubation and ICU stay but do not include rehabilitation expenses which will be the focus of another study. We find that our institution, which likely reflects many institutions in our OPO, serves sicker patients and therefore incurs higher costs but receives lower reimbursements, as they are based on national expected care costs for healthier patients. A broader sharing in the US may equalize costs. Payers should take into account the added financial burden of performing transplant in high MELD patients