Transplantation最新文献

Background: This study evaluated the efficacy of an optimized immunosuppressive regimen, including a higher dose of anti-CD154 monoclonal antibody (TNX-1500), in prolonging graft survival in pig-to-baboon kidney xenotransplantation. Despite advances in genetic engineering of organ-source pigs and immunosuppressive regimens, we report that the development of nephrotic-range proteinuria remains a significant problem.

Methods: We assessed the TNX-1500-based immunosuppressive regimen in 9 baboon recipients of gene-edited pig kidney transplants. The regimen included induction with antithymocyte globulin, anti-CD20 monoclonal antibody (rituximab), and C1 esterase inhibitor, and maintenance with TNX-1500, rapamycin, methylprednisolone, and anti-interleukin-6 receptor blockade (tocilizumab).

Results: Although an increased dose of TNX-1500 of 30 mg/kg (higher dose, n = 6) versus 20 mg/kg (lower dose, n = 3) improved overall survival (median 214 versus 86 d; P  < 0.05), 4 of 9 baboons (including 3 with higher dose) developed persistent nephrotic-range proteinuria. The histopathology of these 4 grafts revealed focal glomerular thrombotic microangiopathy (4/4), transplant glomerulopathy (3/4), focal segmental glomerulosclerosis (2/4), and/or membranous nephropathy (1/4) but no definitive features of rejection. Proteinuria was associated with decreased serum albumin and, very importantly, with loss of TNX-1500 in the urine.

Conclusions: Despite the efficacy of the immunosuppressive regimen, we suggest that proteinuria may lead to inadequate immunosuppressive therapy through loss of the therapeutic antibody, thus increasing the risk of rejection. Further research is needed to develop strategies to prevent this complication.

Background: BK polyomavirus (BKPyV) nephropathy is a significant complication of kidney transplantation associated with high levels of BKPyV replication in plasma and poor graft survival. It is currently treated by reducing immunosuppression to restore the immune response.

Methods: We analyzed circulating T cells from 28 kidney transplant recipients with detectable levels of BKPyV DNA in the blood (BKPyV DNAemia). Immunosuppression was significantly reduced in all these patients. We evaluated BKPyV-specific T-cell functionality and phenotype and assessed graft outcomes prospectively.

Results: BKPyV DNAemia was rapidly controlled in 13 patients (controllers [C] group), whereas viral replication was sustained in the other 15, who were considered not to have responded to reduced immunosuppression (noncontroller [NC] group). The induction and maintenance therapies used were similar in the C and NC groups. The slope of renal function decline tended to be worse in the NC group than in the C group ( P  < 0.055). BKPyV-specific T-cell functions (T-cell proliferation and cytokine secretion) were weaker in the NC group than in the C group. This functional impairment was associated with an overexpression of several inhibitory receptors (programmed cell death protein 1 [PD1], T-cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, or T-cell immunoglobulin and mucin-containing protein 3 [TIM3]), highlighting an exhausted-like phenotype of BKPyV-specific CD4 and CD8 T cells in the NC group. T-cell inhibition was not overcome by a single blocking antibody against inhibitory receptors, whereas a combination of anti-PD1 and anti-TIM3 antibodies significantly restored BKPyV-specific CD8 T-cell functions ( P  < 0.05).

Conclusions: Sustained BKPyV DNAemia was associated with an exhausted phenotype of BKPyV-specific T cells despite immunosuppression reduction in kidney transplant recipients. We show that anti-BKPyV-specific CD8 functions can be restored ex vivo by blocking the PD1 and TIM3 pathways, paving the way for new treatment strategies.

Background: Acute rejection (AR) remains a major determinant of renal allograft outcomes, with the major histocompatibility complex (MHC) playing a pivotal role in its pathogenesis. Although immunosuppressive therapies have advanced, their reliance on high doses and lifelong administration increases the risks of infections, malignancies, and other serious complications. Normothermic machine perfusion (NMP) has emerged as a valuable tool in clinical transplantation, enabling organ preservation, functional assessment, and therapeutic intervention. Integrating NMP with genetic engineering approaches to modulate donor kidney MHC expression may offer a novel strategy for preventing AR.

Methods: We synthesized cholesterol-modified small interfering RNA targeting B2m and Ciita (si B2m -Chol and siCiita -Chol) and set cholesterol-modified negative control small interfering RNA (siNC-Chol) as control. Interfering with MHC expression in transplanted kidneys using NMP combined with siB2m-Chol and siCiita-Chol pretreatment of donor kidneys to prevent AR of posttransplant allografts, we evaluated the efficacy of this approach by assessing postoperative survival, renal function, histological features, and inflammatory responses.

Results: NMP combined with siB2m-Chol and siCiita-Chol significantly reduced MHC expression on postoperative day 3, improved allograft function, and prolonged recipient survival. By postoperative day 7, pathological damage was reduced, and T cells, macrophages, B cells, donor-specific antibodies, and inflammatory cytokine production were markedly lower in treated grafts compared with the siNC-Chol control group.

Conclusions: These findings demonstrate that ex vivo NMP effectively delivers cholesterol-modified small interfering RNA to renal grafts, substantially downregulating both MHC class I and II expression and consequently attenuating AR.

Background: The mandatory 6-mo waiting period implemented in 2015 for accruing model for end-stage liver disease exception points in patients with early-stage hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) has been associated with improved outcomes. However, most of these findings are dependent on cohorts who have had access to the OLT waitlist, and the policy's impact on non-OLT treatment strategies (eg, liver resection, ablation) remains poorly understood.

Methods: This was a retrospective analysis of patients with early-stage HCC (T2N0M0) from the National Cancer Database from 2010 to 2021. The pre-/post-policy era was defined by HCC diagnosis before or after 2015, respectively. The Kaplan-Meier survival method and multivariable Cox proportional hazard regression were used to estimate survival.

Results: Among 53 928 patients, rates of OLT decreased (13.1%-7.4%), ablation increased (19.1%-25.3%), and resection remained constant (9.2% versus 9.2%) from the pre- to post-policy era ( P  < 0.001 for all). OLT was associated with the highest 5-y postoperative survival (79.7%), followed by resection (63.5%) and ablation (42.9%; P  < 0.001, all pairwise comparisons). Overall survival improved in the post-policy era (hazard ratio, 0.89; 95% confidence interval, 0.87-0.92), with resection having the greatest improvement in survival (hazard ratio, 0.69; 95% confidence interval, 0.62-0.77). Among all treatment modalities, time-to-intervention was not a predictor of mortality ( P  > 0.05).

Conclusions: Overall, the post-policy era was associated with improved outcomes in early-stage HCC. While survival outcomes between policy eras were similar for OLT or ablation, liver resection was shown to have the highest improvement in survival and remains a durable treatment option in early-stage HCC.