Transplantation Direct最新文献

Background: Alloprimed antibody-suppressor CXCR5⁺CD8⁺ T cells (CD8⁺ T_Ab-supp cells) downregulate alloantibody production, mediate cytotoxicity of IgG⁺ B cells, and prolong allograft survival. The purpose of this investigation was to determine which immune-cell subsets are susceptible to CD8⁺ T_Ab-supp cell-mediated cytotoxicity or noncytotoxic suppression.

Methods: Alloprimed immune-cell subsets were evaluated for susceptibility to CD8⁺ T_Ab-supp cell-mediated in vitro cytotoxicity and/or suppression of intracellular cytokine expression. In vivo CD8-mediated cytotoxicity to wild-type germinal center (GC) B cells or wild-type CD4⁺ T follicular helper cells (T_FH cells) was assessed in RAG1 knockout mice. The impact of in vivo adoptive transfer of CD8⁺ T_Ab-supp cells into hepatocyte or kidney transplant recipients on the quantity of lymphoid immune-cell subsets was assessed.

Results: CD8⁺ T_Ab-supp cells mediated allospecific cytotoxicity to alloprimed GC B cells but not alloprimed extrafollicular plasmablasts, marginal zone B cells, follicular B cells, or plasma cells. CD8⁺ T_Ab-supp cells did not mediate cytotoxicity to alloprimed dendritic cells, macrophages, CD4⁺ T_FH cells, CD4⁺ T follicular regulatory cells, or CD4⁺ regulatory T cell. CD8⁺ T_Ab-supp cells did not suppress CD4⁺ T_FH cell, T follicular regulatory cell, or regulatory T-cell cytokine expression. Adoptive transfer of CD8⁺ T_Ab-supp cells into hepatocyte or kidney transplant recipients reduced alloantibody production and the quantity of GC B cells, T_FH cells, and plasma cells (but not other B-cell, T-cell, or antigen-presenting cell subsets). The reduction of T_FH-cell quantity was dependent on CD8⁺ T_Ab-supp cell-mediated major histocompatibility complex-I-dependent cytotoxic killing of GC B cells.

Conclusions: The primary targets of CD8⁺ T_Ab-supp cells are GC B cells with downstream reduction of T_FH and plasma cells.

Background: The limitations of conventional measures of socioeconomic status (SES) limit our ability to elucidate the role of SES as a key element of social determinants of health in kidney transplantation. This study's objective was to use an innovative SES measure, the HOUsing-based SES measure (HOUSES) index, to examine the effects of social determinants of health on access to and outcomes of kidney transplantation.

Methods: Our study included residents of Minnesota (age older than 18 y) who underwent kidney transplantation at a single center between 2010 and 2020. SES was determined using the HOUSES index, categorized into quartiles (Q1 for lower, Q2-Q4 for higher SES). We used mixed-effects multivariable logistic and Cox models to examine the effects of HOUSES on preemptive transplants, pretransplant dialysis duration, and death-censored graft loss, adjusting for covariates.

Results: Among 1975 eligible patients, 29.4% received preemptive transplants, 34.9% underwent pretransplant dialysis for >3 y, and 15.1% experienced death-censored graft loss for a median follow-up of 7.15 (interquartile range, 4.25-11.38) y. Lower SES recipients (Q1) demonstrated decreased preemptive transplant likelihood (adjusted odds ratio [aOR]: 0.74; 95% confidence interval [CI], 0.57-0.97; P = 0.03), longer dialysis duration (>3 y; aOR: 1.43; 95% CI, 1.01-2.03; P = 0.046), and higher death-censored graft loss (adjusted hazard ratio 1.36; 95% CI, 1.02-1.12; P = 0.036) versus higher SES recipients (Q2-Q4).

Conclusions: We observed significant socioeconomic disparities in kidney transplant access, dialysis duration, and graft survival. The HOUSES index may be a promising tool for individual-based targeted interventions as it identifies SES on an individual rather than an area-level basis.

Background: Deceased donor multiorgan transplants utilizing kidneys (MOTs) can improve outcomes for multiorgan recipients but reduces kidneys for chronic renal failure patients.

Methods: We reviewed the Organ Procurement and Transplantation Network database from 2015 through 2019, for adult deceased donor kidney transplants. Recipients were classified as kidney transplant alone (KTA) (n = 62,252) or MOTs pancreas-kidney, simultaneous pancreas-kidney (n = 3,976), liver-kidney, simultaneous liver-kidney (n = 3,212), heart-kidney, simultaneous heart-kidney (n = 808), and "other"-kidney, simultaneous "other" kidney (n = 73).

Results: Liver, heart, and lung-alone transplants were at least 7 times more frequent than their MOT correlate, whereas the inverse was true with pancreas transplantation with SPKs being by far the most common pancreas transplant type. On average, KTA recipients waited between 2.8 and 21.4 times longer than MOTs, with SPKs waiting the longest of the MOT types. Predialysis initiation transplants were less frequent in KTAs compared with MOTs. Use of high-quality grafts according to Kidney Donor Profile Index < 35% was frequent among MOTs, but uncommon in KTAs who had an Estimated Post Transplant Survival score (EPTS) of >20%. For recipients older than 65, SPKs and SOKs were rare, but SLKs and SHKs had a higher fraction of recipients than KTAs and were much more likely to use a Kidney Donor Profile Index <35% kidney. SPKs and KTAs with an EPTS ≤20% had the best kidney graft survival. KTAs with an EPTS ≤80% had better kidney graft survival than SLKs, SHKs, and SOKs.

Conclusions: This study highlights disparities in access to deceased donor kidneys for kidney-alone candidates versus MOTs and suggests opportunities to improve allocation.

Background: Perioperative intravenous fluids are administered to kidney transplant recipients to maintain hemodynamic stability and graft perfusion; however, the ideal fluid remains uncertain. Although 0.9% saline (saline) is commonly used, its high chloride content causes hyperchloremic metabolic acidosis and may increase the risks of delayed graft function (DGF) and hyperkalemia. Balanced electrolyte solutions (BES) have a more physiological chloride concentration and may reduce these risks. Previous meta-analyses found insufficient evidence to compare BES with saline for these outcomes; however, new studies have recently been published. In this updated review, we compared the effects of BES with saline on the risk of DGF and hyperkalemia in kidney transplantation.

Methods: MEDLINE, Embase, and CENTRAL were searched for randomized controlled trials comparing BES with saline in kidney transplantation. The primary outcomes were DGF and hyperkalemia. Eligible studies were assessed for risk of bias and data were pooled for analysis. The Grading of Recommendations Assessment, Development, and Evaluation framework was used to assess the quality of evidence.

Results: Ten studies involving 1532 participants were included. The quality of evidence was high for deceased donor transplantation and very low for living donor transplantation. The relative risk (RR) of DGF associated with BES compared with saline was 0.83 (95% confidence interval [CI], 0.71-0.96; P = 0.01) in deceased donor transplantation. There was no difference in DGF in living donor transplantation (RR 0.79; 95% CI, 0.26-2.41; P = 0.68). There was no difference in hyperkalemia between groups (RR 0.87; 95% CI, 0.59-1.27; P = 0.46).

Conclusions: Compared with saline, BES reduces the risk of DGF in deceased donor kidney transplantation without increasing hyperkalemia.

Background: Presensitized patients with circulating donor-specific antibodies (DSAs) before transplantation are at risk for antibody-mediated rejection (AMR). Peritransplant desensitization mitigates but does not eliminate the alloimmune response. We examined the possibility that subthreshold AMR activity undetected by histology could be operating in some early biopsies.

Methods: Transcriptome of kidney allograft biopsies performed within the first month in presensitized patients (DSA⁺) who had received desensitization and did not develop active/probable AMR by histology (R^-) was compared with biopsies showing active/probable AMR (R⁺/DSA⁺). As negative controls, biopsies without rejection by histology in patients without DSA at transplantation were used (R^-/DSA^-). RNA sequencing from biopsies selected from the biobank was used in cohort 1 (n = 32) and microarray, including the molecular microscope (Molecular Microscope Diagnostic System [MMDx]) algorithm, in recent cohort 2 (n = 30).

Results: The transcriptome of R^-/DSA⁺ was similar to R⁺/DSA⁺ as these groups differed in 14 transcripts only. Contrarily, large differences were found between both DSA⁺ groups and negative controls. Fast gene set enrichment analyses showed upregulation of the immune system in both DSA⁺ groups (gene ontology terms: adaptive immune response, humoral immune response, antigen receptor-mediated signaling, and B-cell receptor signaling or complement activation) when compared with negative controls. MMDx assessment in cohort 2 classified 50% of R^-/DSA⁺ samples as AMR and found no differences in AMR molecular scores between R⁺ and R^- DSA⁺ groups. In imlifidase desensitization, MMDx series showed a gradual increase in AMR scores over time.

Conclusions: Presensitized kidney transplant recipients exhibited frequent molecular calls of AMR in biopsy-based transcript diagnostics despite desensitization therapy and negative histology.

Background: In organ transplantation, cold ischemia is associated with sterile inflammation that subsequently conditions adaptive immunity directed against the grafts during revascularization. This inflammation is responsible for venous thrombosis, which is the main postoperative complication affecting graft function. Our aim was to investigate the modulation of immune responses and endothelial function of pancreatic grafts during cold ischemia using different preservation modalities.

Methods: According to a preclinical porcine model of controlled donation after circulatory death, pancreatic grafts were preserved under hypothermic conditions for 24 h according to 4 modalities: static cold storage, hypothermic machine perfusion, hypothermic oxygenated perfusion at 21%, and 100%. Biopsies of the head and tail of the pancreas were performed during preservation. The first step involved a broad screening of the gene expression profile (84 genes) during preservation on a limited number of grafts. In the second step, a confirmation test was performed in all 4 groups.

Results: Vascular endothelial growth factor gene expression showed a decrease during preservation in the hypothermic oxygenated perfusion 21% and 100% groups compared with the static cold storage group. In contrast, thrombomodulin gene expression showed an increase during preservation in the hypothermic oxygenated perfusion 21% and 100% groups compared with the static cold storage and hypothermic machine perfusion groups.

Conclusions: We demonstrated that compared with static cold storage, hypothermic oxygenated perfusion is an effective modality for modulating endothelial function by increasing thrombomodulin expression and decreasing ischemia and vascular endothelial growth factor expression.

Background: Cardiovascular disease and physical decline are prevalent and associated with morbidity/mortality in liver transplant (LT) patients. Cardiopulmonary exercise testing (CPX) provides comprehensive cardiopulmonary and exercise response assessments. We investigated cardiorespiratory fitness (CRF) and cardiac stress generated during CPX in LT candidates.

Methods: LT candidates at 2 centers underwent CPX. Standard-of-care cardiac stress testing (dobutamine stress echocardiography, DSE) results were recorded. Physical function was assessed with liver frailty index and 6-min walk test. CPX/DSE double products were calculated to quantify cardiac stress. To better study the association of CPX-derived metrics with physical function, the cohort was divided into 2 groups based on 6-min walk test median (372 m).

Results: Fifty-four participants (62 ± 8 y; 65% men, Model for End-Stage Liver Disease-Na 14 [10-18]) underwent CPX. Peak oxygen consumption was 14.1 mL/kg/min for an anerobic threshold of 10.2 mL/kg/min, with further CRF decline in the lower 6MWT cohort despite lack of liver frailty index-frailty in 90%. DSE was nondiagnostic in 18% versus 4% of CPX (P = 0.058). All CPX were negative for ischemia. A double product of ≥25 000 was observed in 32% of CPX and 11% of DSE (P = 0.020). Respiratory function testing was normal. No patient presented major cardiovascular events at 30 d post-LT.

Conclusions: CPX provided efficient and effective combined cardiopulmonary risk and frailty assessments of LT candidates in a 1-stop test. The CRF was found to be very low despite preserved physical function or lack of frailty.

Background: Healthcare-associated infections (HAIs) are preventable complications that overwhelm the healthcare system. The implementation of multifaceted control intervention actions in the intensive care setting modifies clinical outcomes, but its effectiveness has not been specifically investigated for high-risk patients, such as kidney transplant recipients (KTRs).

Methods: This observational retrospective natural experiment evaluated the effectiveness of multifaceted control interventions (bundles) in reducing HAIs in a KTR intensive care unit. We also measured the bundle adherence rate during 16 mo in the after era.

Results: We included 1257 KTRs, 684 before and 573 in the postintervention period. After the bundle implementation, the incidence density of device-associated HAIs decreased from 8.5 to 3.9 per 1000 patient-days (relative risk [RR] = 0.46; 95% confidence interval [CI], 0.25-0.85; P = 0.01), primarily because of the reduction in central line-associated bloodstream infection from 8.0 to 3.4 events per 1000 catheter-days (RR = 0.43; 95% CI, 0.22-0.83; P = 0.012). Reductions in catheter-associated urinary tract infection (2.5 versus 0.6 per 1000 catheter-days; RR = 0.22; 95% CI, 0.03-1.92; P = 0.17) and ventilator-associated pneumonia (3.4 versus 1.0 per 1000 ventilator-days; RR = 0.29; 95% CI, 0.03-2.63; P = 0.27) were not significant. Central venous (P = 0.53) and urinary catheter (P = 0.47) insertion adherence were stable during 16 mo, whereas central venous (P < 0.001) and urinary catheter (P = 0.004) maintenance gradually increased. Finally, ventilator-associated pneumonia prevention bundle adherence slightly decreased over time (P = 0.06).

Conclusions: The implementation of comprehensive multifaceted control intervention actions in an intensive care unit dedicated to KTR care was effective in significantly reducing device-associated infections. The impact was in line with the reductions observed in populations that have not undergone transplantation, underscoring the effectiveness of these interventions across different patient groups.

Post-transplant lymphoproliferative disorders (PTLDs) remain a feared complication of transplantation, with significant morbidity and mortality. The oncogenic Epstein-Barr virus (EBV) is a key pathogenic driver in 50%-80% of cases. Numerous prognostic indices, comprising multiple clinical, epidemiological and tumor characteristics, including EBV tumor positivity, do not consistently associate with worse patient survival, suggesting a potential role for EBV genome variants in determining outcome. However, the precision medicine tools for determining if a viral genome variant is pathogenic are very limited compared with human genome variants. Further, targeted studies have not implicated a specific viral etiological agent in EBV-negative PTLD. Using novel cutting-edge technologies, we are extracting viral nucleic acids from formalin-fixed, paraffin-embedded archived, or frozen PTLD tissues or plasma, to test for all vertebrate viruses simultaneously in an unbiased fashion, using metagenomic shotgun sequencing (MSS). We are collecting such samples from multiple transplant centers to address the following specific aims and close the following knowledge gaps: (1) Validate our novel observation that PTLD tissue positivity by MSS for anellovirus (and confirmed by PCR) serves as a biomarker for higher transplant recipient mortality after the diagnosis of PTLD; (2) determine the role of other oncogenic viruses in EBV-negative PTLD by unbiased MSS of multiple viral groupings, confirmed by other techniques; and (3) develop the necessary computational, algorithmic and software analytic tools required to determine association of EBV genome variants with worse presentations or outcomes in PTLD. Study completion will contribute to better patient care and may provide avenues for novel therapies.

Background: There are limited data about the risk factors for weight changes and the association of significant weight changes with graft and metabolic outcomes after simultaneous pancreas and kidney (SPK) transplantation.

Methods: We included all SPK recipients with both allografts functioning for at least 6 mo post-transplant and categorized them based on the weight changes from baseline to 6 mo post-transplant. We analyzed risk factors for significant weight gain (SWG) and significant weight loss (SWL) over 6 mo post-transplant, as well as outcomes including pancreas uncensored graft failure, pancreas death-censored graft failure (DCGF), composite pancreas graft outcomes of DCGF, use of an antidiabetic agent, or hemoglobin A1C >6.5%, and kidney DCGF.

Results: Of 280 SPK recipients, 153 (55%) experienced no significant weight change, 57 (20%) SWG, and 70 (25%) SWL. At 6 mo post-transplant, mean weight changes were 1.2% gain in the no significant weight change group, 13.4% gain in SWG, and 9.6% loss in the SWL groups. In multivariate analysis, the only factor associated with decreased risk for weight gain was older recipient age (aOR, 0.97; 95% confidence intervals, 0.95-0.99). Importantly, SWG or SWL were not associated with pancreas graft failure, P-DCGF, or K-DCGF. Interestingly in the adjusted model, SWG at 6 mo was associated with a lower risk for composite outcomes (HR, 0.35; 95% confidence intervals, 0.14-0.85).

Conclusions: Forty-five percent of SPK recipients had significant weight changes by 6 mo post-transplant, but only 20% exhibited SWG. Likely because of proper management, weight changes were not associated with poor outcomes post-SPK transplant.