Long-term Graft and Patient Survival after Balloon Dilation of Ureteric Stenosis after Renal Transplant: A 23-year Retrospective Matched Cohort Study.

Purpose To study long-term graft and patient survival after percutaneous ureteroplasty of ureteric stenosis after renal transplantation and to compare the outcomes to those of patients who did not develop ureteric stenosis. Materials and Methods An ethical waiver was obtained for this 23-year retrospective matched cohort study of 52 of 1476 consecutive kidney transplant recipients who developed postoperative ureteric stenosis. Data were collected between January 1990 and December 2012. All patients (mean age, 47 years [range, 23-72 years]; 36 men aged 29-72 years [mean age, 49 years] and 24 women aged 23-68 years [mean age, 42 years]) underwent percutaneous ureteroplasty; recurrent stenosis was managed surgically or by means of long-term ureteric stent placement. Outcomes were compared with those of a matched control group of transplant recipients with no history of ureteric stenosis. Primary outcome measures were death-censored graft failure and all-cause mortality. Secondary outcome measures were the effect of time of stricture onset on graft survival, complications, and risk factors for recurrent stenosis. Kaplan-Meier curves were compared by using log-rank tests, with P < .05 indicative of a statistically significant difference. Results Balloon dilation was technically successful in all 52 strictures, but stenosis recurred in 10 patients and was treated with surgery (n = 5) or long-term stent placement (n = 5). The 10-year graft and patient survival were not significantly different in study versus control groups, with graft survival of 64.5% (95% confidence interval [CI]: 43.4%, 79.4%) versus 76.3% (95% CI: 58.6%, 87.2%), respectively (P = .372), and patient survival of 82.2% (95% CI: 62.9%, 92%) versus 89.9% (95% CI: 74.6%, 96.2%) (P = .632). Subgroup analysis showed that stenosis occurring less than 3 months (10-year graft survival, 59.1%), at least 3 months (10-year graft survival, 67.3%), and at least 6 months (10-year graft survival, 53.0%) after transplantation did not adversely affect graft survival compared with that of the control group (P > .05). Cold ischemia time was longer in those with recurrent stenosis than in control subjects (16.1 vs 8.4 hours, respectively; P = .034). The minor and major complication rates were 13% and 5.7%, respectively, with no 30-day graft loss and patient mortality. Conclusion Long-term graft and patient survival in patients with percutaneous ureteroplasty of transplant ureteric stenosis were not significantly worse than those in a control group. (©) RSNA, 2016.

Protease-activated receptor-2 signalling by tissue factor on dendritic cells suppresses antigen-specific CD4+ T-cell priming.

The precise function of tissue factor (TF) expressed by dendritic cells (DC) is uncertain. As well as initiating thrombin generation it can signal through protease-activated receptor 2 (PAR-2) when complexed with factor VIIa. We investigated the expression and function of TF on mouse bone marrow (BM) -derived DC; 20% of BM-derived DC expressed TF, which did not vary after incubation with lipopolysaccharide (LPS) or dexamethasone (DEX). However, the pro-coagulant activity of DEX-treated DC in recalcified plasma was 30-fold less than LPS-treated DC. In antigen-specific and allogeneic T-cell culture experiments, the TF on DEX-treated DC provided a signal through PAR-2, which contributed to the reduced ability of these cells to stimulate CD4(+) T-cell proliferation and cytokine production. In vivo, an inhibitory anti-TF antibody and a PAR-2 antagonist enhanced antigen-specific priming in two models where antigen was given without adjuvant, with an effect approximately 50% that seen with LPS, suggesting that a similar mechanism was operational physiologically. These data suggest a novel TF and PAR-2-dependent mechanism on DEX-DC in vitro and unprimed DC in vivo that contributes to the low immunogenicity of these cells. Targeting this pathway has the potential to influence antigen-specific CD4(+) T-cell activation.

Inhibition of thrombin receptor signaling on α-smooth muscle actin(+) CD34(+) progenitors leads to repair after murine immune vascular injury.

OBJECTIVE: The goal of this study was to use mice expressing human tissue factor pathway inhibitor (TFPI) on α-smooth muscle actin (α-SMA)(+) cells as recipients of allogeneic aortas to gain insights into the cellular mechanisms of intimal hyperplasia (IH). METHODS AND RESULTS: BALB/c aortas (H-2(d)) transplanted into α-TFPI-transgenic (Tg) mice (H-2(b)) regenerated a quiescent endothelium in contrast to progressive IH seen in C57BL/6 wild-type (WT) mice even though both developed aggressive anti-H-2(d) alloresponses, indicating similar vascular injuries. Adoptively transferred Tg CD34(+) (but not CD34(-)) cells inhibited IH in WT recipients, indicating the phenotype of α-TFPI-Tg mice was due to these cells. Compared with syngeneic controls, endogenous CD34(+) cells were mobilized in significant numbers after allogeneic transplantation, the majority showing sustained expression of tissue factor and protease-activated receptor-1 (PAR-1). In WT, most were CD45(+) myeloid progenitors coexpressing CD31, vascular endothelial growth factor receptor-2 and E-selectin; 10% of these cells coexpressed α-SMA and were recruited to the neointima. In contrast, the α-SMA(+) human TFPI(+) CD34(+) cells recruited in Tg recipients were from a CD45(-) lineage. WT CD34(+) cells incubated with a PAR-1 antagonist or taken from PAR-1-deficient mice inhibited IH as Tg cells did. CONCLUSIONS: Specific inhibition of thrombin generation or PAR-1 signaling on α-SMA(+) CD34(+) cells inhibits IH and promotes regenerative repair despite ongoing immune-mediated damage.

Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients: a potential role for CD8+ T-cell modulation by carbon monoxide.

BACKGROUND: Induction of heme oxygenase (HO)-1 expression protects transplanted organs from humoral rejection and ischemia-reperfusion injury, but induction in recipient immune cells also has direct immunomodulatory effects. Although many studies have examined the impact of HO-1 after transplantation, it is still unclear whether HO-1 expression solely in the donor tissue can influence the recipient T-cell response. METHODS: Donor mice were treated with hemin to transiently upregulate HO-1. Control or HO-1-expressing aortas were transplanted into fully mismatched, completely unmanipulated recipients, and harvested at 6 weeks to assess neointimal area and T-cell infiltration. T cells were isolated from draining lymph nodes to assess cytokine production. In vitro, T-cell proliferative and cytokine responses to allogeneic donor dendritic (DC) and endothelial cells expressing HO-1 were examined. RESULTS: Neointimal area was significantly (P<0.01) reduced in HO-1-expressing grafts. Hemin pretreated endothelial cells significantly inhibited proliferation (P<0.01) and interferon (IFN)-gamma production (P =0.01) in allogeneic CD8 T cells. This effect was mimicked by a carbon monoxide-releasing molecule. No phenotypic or functional changes were observed after incubation of T cells with hemin-treated dendritic cells. T-cell infiltration of HO-1-expressing donor aortas was significantly reduced (P<0.001), but proportions of IFN-gamma-producing T cells harvested from regional lymph nodes were similar. CONCLUSIONS: Organs expressing cytoprotective HO-1 have a direct influence on the recipient immune response. Given the important role of CD8 T cells and IFN-gamma in chronic rejection, these data suggest that donor HO-1 expression may be useful to augment other immunosuppressive therapies to prolong graft survival and inhibit intimal hyperplasia.