Madison C. Cuffy

Induction of Indoleamine 2,3-Dioxygenase in Vascular Smooth Muscle Cells by Interferon-γ Contributes to Medial Immunoprivilege

Atherosclerosis and graft arteriosclerosis are characterized by leukocytic infiltration of the vessel wall that spares the media. The mechanism(s) for medial immunoprivilege is unknown. In a chimeric humanized mouse model of allograft rejection, medial immunoprivilege was associated with expression of IDO by vascular smooth muscle cells (VSMCs) of rejecting human coronary artery grafts. Inhibition of IDO by 1-methyl-tryptophan (1-MT) increased medial infiltration by allogeneic T cells and increased VSMC loss. IFN-γ-induced IDO expression and activity in cultured human VSMCs was considerably greater than in endothelial cells (ECs) or T cells. IFN-γ-treated VSMCs, but not untreated VSMCs nor ECs with or without IFN-γ pretreatment, inhibited memory Th cell alloresponses across a semipermeable membrane in vitro. This effect was reversed by 1-MT treatment or tryptophan supplementation and replicated by the absence of tryptophan, but not by addition of tryptophan metabolites. However, IFN-γ-treated VSMCs did not activate allogeneic memory Th cells, even after addition of 1-MT or tryptophan. Our work extends the concept of medial immunoprivilege to include immune regulation, establishes the compartmentalization of immune responses within the vessel wall due to distinct microenvironments, and demonstrates a duality of stimulatory EC signals versus inhibitory VSMC signals to artery-infiltrating T cells that may contribute to the chronicity of arteriosclerotic diseases.

Recruitment of CXCR3+ and CCR5+ T Cells and Production of Interferon‐γ‐Inducible Chemokines in Rejecting Human Arteries

Chemokine receptors preferentially expressed by Th1 cells and their IFN‐γ‐inducible ligands predominate in experimental and clinical allograft rejection. Previous chemokine‐related transplantation studies have focused on parenchymal and microvascular inflammation which are of importance in acute rejection, but are not necessarily relevant in immune‐mediated injury of conduit arteries. We have recently described a model of progressive human T cell‐mediated infiltration and injury of allogeneic coronary artery segments using immunodeficient mouse hosts. In the present study, we investigated if recruitment of allogeneic T cells to different vascular compartments correlated with the expression of chemokines and their receptors. Transcripts were quantified by laser capture microdissection/real‐time RT‐PCR and their distribution was correlated to the corresponding protein expression detected by immunohistochemistry. Infiltrating T cells, confined to the adventitia and intima, expressed CXCR3 and CCR5, but were not recruited into the media despite production by vascular smooth muscle cells of IP‐10, Mig, I‐TAC, RANTES and MIP‐1β. Chemokine mRNA was detected primarily in vascular cells, although chemokine protein largely localized to infiltrating leukocytes which uniquely expressed their cognate receptors. These data explain the recruitment of IFN‐γ‐secreting T cells to the vessel wall, and reinforce the suggestion that the arterial media may be a site of immunological privilege.

Impact of recipient morbid obesity on outcomes after liver transplantation

The aim of this study was to analyze the impact of morbid obesity in recipients on peritransplant resource utilization and survival outcomes. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 12 445 patients who underwent liver transplantation (LT) between 2007 and 2011 and divided them into two cohorts based on recipient body mass index (BMI; <40 vs. ≥40 kg/m²). Recipients with BMI ≥40 comprised 3.3% (n = 416) of all LTs in the studied population. There were no significant differences in donor characteristics between two groups. Recipients with BMI ≥40 were significant for being female, diabetic, and with NASH cirrhosis. Patients with a BMI ≥40 had a higher median MELD score, limited physical capacity, and were more likely to be hospitalized at LT. BMI ≥40 recipients had higher post‐LT length of stay and were less often discharged to home. With a median follow‐up of 2 years, patient and graft survival were equivalent between the two groups. In conclusion, morbidly obese LT recipients appear sicker at time of LT with an increase in resource utilization but have similar short‐term outcomes.

Desensitization in kidney transplantation: review and future perspectives.

More than half of the kidney transplant candidates awaiting transplantation are sensitized to human leukocyte antigens (HLAs). Desensitization to HLAs involves treatment with immunomodulating therapies designed to reduce levels of anti‐HLA antibodies in order to make kidney transplantation possible. Over the last two decades, desensitization therapies have been limited to plasmapheresis (PP), immunoadsorption (IA), intravenous immunoglobulins (IVIg), and rituximab. Review of reported experiences with desensitization in kidney transplant candidates revealed that PP or IA alone is inadequate to achieve durable reductions in HLA antibodies. Increasing evidence has accumulated indicating that high‐dose IVIg has limited ability to reduce HLA antibodies, but a few centers have reported success with high‐dose IVIg+rituximab in non‐randomized trials. Overall experience in multiple centers, however, has shown high antibody‐mediated rejection (AMR) rates, particularly in patients with the highest degrees of HLA sensitization. Low‐dose IVIg combined with alternate day PP in living donor transplant candidates has been shown to provide enhanced survival over dialysis. However, low‐dose IVIg/PP regimens also continue to be associated with unacceptable AMR rates. Recent experiences with plasma cell‐targeted therapies based on the proteasome inhibitor bortezomib are relatively small but may represent an important alternative to non‐deletional strategies with IVIg.

Addressing Morbid Obesity as a Barrier to Renal Transplantation With Laparoscopic Sleeve Gastrectomy

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25‐month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m2 (range 35.8–67.7 kg/m2). Follow‐up after LSG was 220 ± 152 days (range 26–733 days) with last BMI of 36.3 ± 5.3 kg/m2 (range 29.2–49.8 kg/m2) with 29 (55.8%) patients achieving goal BMI of <35 kg/m2 at 92 ± 92 days (range 13–420 days). The mean percentage of excess weight loss (%EWL) was 32.1 ± 17.6% (range 6.7–93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m2/month versus 1.1 kg/m2/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti‐hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach.

Renal transplantation for nephrogenic systemic fibrosis: a case report and review of the literature

Nephrogenic systemic fibrosis (NSF) is a rare fibrosing disorder described among patients with renal disease. Currently, no standard therapy exists, although therapeutic modalities have included plasmapheresis, extracorporeal photopheresis, sodium thiosulphate, imatinib and renal transplantation. We describe a patient with NSF who was physically debilitated and underwent renal transplantation. After transplantation, the patients lesions improved clinically, and the patient was ambulatory. Despite developing worsening renal function, her lesions remained unchanged. We conclude that renal transplantation improves symptoms of NSF, and believe that in patients with NSF, careful consideration should be made for early renal transplantation.

Hepatitis C transmission from seropositive, nonviremic donors to non–hepatitis C liver transplant recipients

Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody–positive but serum nucleic acid test (NAT)–negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody–negative (n = 25) or NAT‐negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody–positive but serum NAT‐negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow‐up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct‐acting antiviral therapy, with two achieving a sustained virologic response and one an end‐of‐treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy. Conclusion: In this prospective cohort of non‐HCV liver recipients receiving grafts from HCV antibody–positive/NAT‐negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673‐1682).

Equipoise: Ethical, Scientific, and Clinical Trial Design Considerations for Compatible Pair Participation in Kidney Exchange Programs

Compatible living donor/recipient pair participation (CPP) in kidney exchange (KE) transplantation may substantially increase transplant volumes and significantly mitigate the O blood group donor shortage in KE. Initial ethical analysis did not support CPP for two primary reasons: (1) KE would be “unbalanced,” and (2) the possibility of undue influence experienced by the compatible pair living donor. Recent developments with CPP (modeling studies and small clinical experiences), have demonstrated substantial potential for increasing KE volumes. This encouraged us to reconsider initial ethical concerns, with a focus on the potential for a design of a prospective CPP clinical trial. This ethical reconsideration led us to conclude that the concept of unbalanced kidney exchanges (manifested primarily by differential benefit between compatible and incompatible pairs) is no longer as clear cut as originally conceived. In addition, application of two concepts substantially diminishes ethical concerns including: (1) “quasi‐compatible” pairs, and (2) a priori definition of mitigating factors. We conclude that genuine uncertainty exists regarding whether kidney exchange is best performed with or without compatible pair participation and that a clinical trial is therefore warranted.

Independent effect of black recipient race on short-term outcomes after liver transplantation

BACKGROUND Previous studies have demonstrated worse graft and patient survival for black patients after liver transplantation (LT), but these studies have not accounted properly for recipient, donor, center, or geographic effects. In this study, we evaluated the effect of candidate race on patient and graft survival after LT. METHODS Using a novel linkage of the databases of the University Health System Consortium and the US Census and Scientific Registry of Transplant Recipients, we identified 12,445 patients (43.1% of total) who underwent LT in the United States from 2007 to 2011. Using a mixed-effects, proportional hazards model, we assessed the effect of race on patient and graft survival after controlling for recipient, donor, and center characteristics; region; donor service area; and individual transplant centers. RESULTS At the time of transplantation, white patients were healthier, had a shorter duration of hospital stay, and a lesser in-hospital mortality compared with black and Hispanic patients. White recipients had a graft and patient survival advantage when compared with blacks, but there was no survival difference observed when compared with Hispanics. After controlling for recipient and donor characteristics, geographic region, donor service area, and the effect of the individual hospital, black recipients were still at an increased risk of both death (hazard ratio [HR], 1.31; 95% CI, 1.15-1.50) and graft failure (HR, 1.28; 95% CI, 1.14-1.44) after LT. CONCLUSION After controlling for many of the important variables in the transplant process, including the individual hospital, black recipients were at increased risk of both death and graft failure after LT when compared with whites.

Use of Elderly Allografts in Liver Transplantation.

Introduction The use of liver allografts from elderly donors (≥70 years) has increased because of organ shortage and increased life expectancy. The aim of this study is to evaluate the current utilization of elderly donors in United States, recipient selection, and their posttransplant outcomes. Methods A linkage between Scientific Registry of Transplant Recipients and University HealthSystem Consortium databases was performed. Between January 2007 and December 2011, 12,445 liver transplant (LT) recipients were identified and divided into 2 cohorts based on donor age: 70 years or older (n = 540) and younger than 60 years (n = 10,473). Results Elderly donors accounted for 4.3% of all donors used in the 5-year period. When compared to younger donors, elderly donors were more likely to be women, shared regionally or nationally, and used at higher volume centers. Elderly donor allografts were less likely to be used in recipients with model of end-stage liver disease score higher than 27 (13.2% vs 23.0%, P < 0.001), hospitalized (16.8% vs 21.7%, P = 0.03), or on hemodialysis at time of transplant (2.6% vs 8.2%, P < 0.001). Both recipient groups had similar perioperative mortality, 30-day readmission rates, and short-term patient survival. In the multivariate analysis, including recipient, donor, center and regional factors, donor age 70 years or older was associated with slightly increased risk of graft loss (hazard ratio, 1.3; 95% confidence interval, 1.08–1.56; P = 0.005). Conclusions The current trend toward the use of elderly donors in liver transplant recipients with low model of end-stage liver disease scores (<27), without hepatitis C, not hospitalized and not on dialysis, is associated with acceptable perioperative outcomes, patient survival, and slightly worse graft survival.