Novel approaches for long-term lung transplant survival.
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ABSTRACT:
SUBMITTER: Miller CL
PROVIDER: S-EPMC9363671 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
Novel approaches for long-term lung transplant survival.
Miller Cynthia L CL O Jane M JM Allan James S JS Madsen Joren C JC
Frontiers in immunology 20220727
Allograft failure remains a major barrier in the field of lung transplantation and results primarily from acute and chronic rejection. To date, standard-of-care immunosuppressive regimens have proven unsuccessful in achieving acceptable long-term graft and patient survival. Recent insights into the unique immunologic properties of lung allografts provide an opportunity to develop more effective immunosuppressive strategies. Here we describe advances in our understanding of the mechanisms driving ...[more]
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Project description:ImportanceThe mortality rate for individuals on the wait list for lung transplant is 15% to 25%, and still only 20% of lungs from multiorgan donors are used for lung transplant. The lung donor pool may be increased by assessing and reconditioning high-risk extended criteria donor lungs with ex vivo lung perfusion (EVLP), with similar short-term outcomes.ObjectiveTo assess the long-term outcomes of transplant recipients of donor lungs treated with EVLP.Design, setting, and participantsThis retrospective cohort single-center study was conducted from August 1, 2008, to February 28, 2017, among 706 recipients of donor lungs not undergoing EVLP and 230 recipients of donor lungs undergoing EVLP.ExposureDonor lungs undergoing EVLP.Main outcomes and measuresThe incidence of chronic lung allograft dysfunction and allograft survival during the 10-year EVLP era were the primary outcome measures. Secondary outcomes included donor characteristics, maximum predicted percentage of forced expiratory volume in 1 second, acute cellular rejection, and de novo donor-specific antibody development.ResultsThis study included 706 patients (311 women and 395 men; median age, 50 years [interquartile range, 34-61 years]) in the non-EVLP group and 230 patients (85 women and 145 men; median age, 46 years [interquartile range, 32-55 years]) in the EVLP group. The EVLP group donors had a significantly lower mean (SD) Pao2:fraction of inspired oxygen ratio than the non-EVLP group donors (348 [108] vs 422 [88] mm Hg; P < .001), higher prevalence of abnormal chest radiography results (135 of 230 [58.7%] vs 349 of 706 [49.4%]; P = .02), and higher proportion of smoking history (125 of 204 [61.3%] vs 322 of 650 [49.5%]; P = .007). More recipients in the EVLP group received single-lung transplants (62 of 230 [27.0%] vs 100 of 706 [14.2%]; P < .001). There was no significant difference in time to chronic lung allograft dysfunction between the EVLP and non-EVLP group (70% vs 72% at 3 years; 56% vs 56% at 5 years; and 53% vs 36% at 9 years; log-rank P = .68) or allograft survival between the EVLP and non-EVLP groups (73% vs 72% at 3 years; 62% vs 58% at 5 years; and 50% vs 44% at 9 years; log-rank P = .97) between the 2 groups. All secondary outcomes were similar between the 2 groups.Conclusions and relevanceSince 2008, 230 of 936 lung transplants (24.6%) in the Toronto Lung Transplant Program were performed after EVLP assessment and treatment. Use of EVLP-treated lungs led to an increase in the number of patients undergoing transplantation, with comparable long-term outcomes.
| S-EPMC6802423 | biostudies-literature
Project description:Lung transplantation is an effective therapy for many patients with end-stage lung disease. Few centers across the United States offer this therapy, as a successful lung transplant program requires significant institutional resources and specialized personnel. Analysis of the United Network of Organ Sharing database reveals that the failure rate of new programs exceeds 40%. These data suggest that an accurate assessment of program viability as well as a strategy to continuously assess defined quality measures is needed. As part of strategic planning, regional availability of recipient and donors should be assessed. Additionally, analysis of institutional expertise at the physician, support staff, financial, and administrative levels is necessary. In May of 2007, we started a new lung transplant program at the University of Iowa Hospitals and Clinics and have performed 101 transplants with an average recipient 1-year survival of 91%, placing our program among the top in the country for the past 5 years. Herein, we review internal and external factors that impact the viability of a new lung transplant program. We discuss the use of four prospectively identified quality measures: volume, recipient outcomes, financial solvency, and academic contribution as one approach to achieve programmatic excellence.
| S-EPMC4420186 | biostudies-other
Project description:Heart transplantation is a lifesaving procedure for patients with end-stage heart failure. Despite much effort and advances in the field, current immunosuppressive regimens are still associated with poor long-term cardiac allograft outcomes, and with the development of complications, including infections and malignancies, as well. The development of a novel, short-term, and effective immunomodulatory protocol will thus be an important achievement. The purine ATP, released during cell damage/activation, is sensed by the ionotropic purinergic receptor P2X7 (P2X7R) on lymphocytes and regulates T-cell activation. Novel clinical-grade P2X7R inhibitors are available, rendering the targeting of P2X7R a potential therapy in cardiac transplantation.We analyzed P2X7R expression in patients and mice and P2X7R targeting in murine recipients in the context of cardiac transplantation. Our data demonstrate that P2X7R is specifically upregulated in graft-infiltrating lymphocytes in cardiac-transplanted humans and mice. Short-term P2X7R targeting with periodate-oxidized ATP promotes long-term cardiac transplant survival in 80% of murine recipients of a fully mismatched allograft. Long-term survival of cardiac transplants was associated with reduced T-cell activation, T-helper cell 1/T-helper cell 17 differentiation, and inhibition of STAT3 phosphorylation in T cells, thus leading to a reduced transplant infiltrate and coronaropathy. In vitro genetic upregulation of the P2X7R pathway was also shown to stimulate T-helper cell 1/T-helper cell 17 cell generation. Finally, P2X7R targeting halted the progression of coronaropathy in a murine model of chronic rejection as well.P2X7R targeting is a novel clinically relevant strategy to prolong cardiac transplant survival.
| S-EPMC3569513 | biostudies-literature
Project description: Not available
| S-EPMC10586948 | biostudies-literature
Project description:BackgroundThe estimated long-term survival (EPTS) score is used for kidney allocation. A comparable prognostic tool to accurately quantify EPTS benefit in deceased donor liver transplant (DDLT) candidates is nonexistent.MethodsUsing the Scientific Registry of Transplant Recipients (SRTR) database, we developed, calibrated, and validated a nonlinear regression equation to calculate liver-EPTS (L-EPTS) for 5- and 10-year outcomes in adult DDLT recipients. The population was randomly split (70:30) into two discovery (N = 26,372 and N = 46,329) and validation cohorts (N = 11,288 and N = 19,859) for 5- and 10-year post-transplant outcomes, respectively. Discovery cohorts were used for variable selection, Cox proportional hazard regression modeling, and nonlinear curve fitting. Eight clinical variables were selected to construct the L-EPTS formula, and a five-tiered ranking system was created.FindingsTier thresholds were defined and the L-EPTS model was calibrated (R2 = 0.96 [5-year] and 0.99 [10-year]). Patients' median survival probabilities in the discovery cohorts for 5- and 10-year outcomes ranged from 27.94% to 89.22% and 16.27% to 87.97%, respectively. The L-EPTS model was validated via calculation of receiver operating characteristic (ROC) curves using validation cohorts. Area under the ROC curve was 82.4% (5-year) and 86.5% (10-year).InterpretationL-EPTS has high applicability and clinical utility because it uses easily obtained pre-transplant patients characteristics to accurately discriminate between those who are likely to receive a prolonged survival benefit and those who are not. It is important to evaluate medical urgency alongside survival benefit and placement efficiency when considering the allocation of a scarce resource.FundingThere are no funding sources related to this project.
| S-EPMC9996349 | biostudies-literature
Project description:Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens.Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde.Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss.Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection.
| S-EPMC6054349 | biostudies-literature
Project description:There is a paucity of data on long-term outcomes following visceral transplantation in the contemporary era. This is a single-center retrospective analysis of all visceral allograft recipients who underwent transplant between November 2003 and December 2013 with at least 3-year follow-up data. Clinical data from a prospectively maintained database were used to assess outcomes including patient and graft survival. Of 174 recipients, 90 were adults and 84 were pediatric patients. Types of visceral transplants were isolated intestinal transplant (56.3%), combined liver-intestinal transplant (25.3%), multivisceral transplant (16.1%), and modified multivisceral transplant (2.3%). Three-, 5-, and 10-year overall patient survival was 69.5%, 66%, and 63%, respectively, while 3-, 5-, and 10-year overall graft survival was 67%, 62%, and 61%, respectively. In multivariable analysis, significant predictors of survival included pediatric recipient (P = .001), donor/recipient weight ratio <0.9 (P = .008), no episodes of severe acute rejection (P = .021), cold ischemia time <8 hours (P = .014), and shorter hospital stay (P = .0001). In conclusion, visceral transplantation remains a good option for treatment of end-stage intestinal failure with parenteral nutritional complications. Proper graft selection, shorter cold ischemia time, and improvement of immunosuppression regimens could significantly improve the long-term survival.
| S-EPMC6591067 | biostudies-literature
Project description:Key Points eGFR at 1 year post transplant is an established predictor of graft failure, but the effects of major intercurrent events are not fully known. We assessed the link between 12-month eGFR and long-term graft failure accounting for intercurrent events and competing mortality risks. Acute rejection, cardiovascular events, and infectious events were significant risks; 12-month eGFR remained the dominant driver of graft failure. Visual Abstract Background Estimated glomerular filtration rate (eGFR) at 1 year post transplantation has been shown to be a strong predictor of long-term graft survival. However, intercurrent events (ICEs) may affect the relationship between eGFR and failure risk. Methods The OPTN and USRDS databases on single-organ kidney transplant recipients from 2012 to 2016 were linked. Competing risk regressions estimated adjusted subhazard ratios (SHRs) of 12-month eGFR on long-term graft failure, considering all-cause mortality as the competing risk, for deceased donor (DD) and living donor (LD) recipients. Additional predictors included recipient, donor, and transplant characteristics. ICEs examined were acute rejection, cardiovascular events, and infections. Results Cohorts comprised 25,131 DD recipients and 7471 LD recipients. SHRs for graft failure increased rapidly as 12-month eGFR values decreased from the reference 60 ml/min per 1.73 m2. At an eGFR of 20 ml/min per 1.73 m2, SHRs were 13–15 for DD recipients and 12–13 for LD recipients; at an eGFR of 30 ml/min per 1.73 m2, SHRs were 5.0–5.7 and 5.0–5.5, respectively. Among first-year ICEs, acute rejection was a significant predictor of long-term graft failure in both DD (SHR=1.63, P<0.001) and LD (SHR=1.51, P=0.006) recipients; cardiovascular events were significant in DD (SHR=1.24, P<0.001), whereas non-CMV infections were significant in the LD cohort (SHR=1.32, P=0.03). Adjustment for ICEs did not significantly reduce the association of eGFR with graft failure. Conclusions Twelve-month eGFR is a strong predictor of long-term graft failure after accounting for clinical events occurring from discharge to 1 year. These findings may improve patient management and clinical evaluation of novel interventions.
| S-EPMC9136886 | biostudies-literature
Project description:BackgroundBleeding following lung surgery can lead to reoperation and blood transfusions, potentially impairing outcomes. This study aimed to assess how bleeding complications affect long-term survival and postoperative complications in a nationwide contemporary group of patients undergoing lung resections.MethodsAdult patients who underwent lung resections, for both malignant and nonmalignant diagnoses, between 2013-2021, were included from the Swedish national registry for thoracic surgery. Patients with bleeding complications, defined as requiring reexploration and/or transfusions, were compared to patients without bleeding complications regarding long-term survival and postoperative complications. We used propensity scores and optimal full matching to account for differences in baseline characteristics between the groups.ResultsThe cohort comprised 15,617 adult patients, of which 646 patients (4.1%) had bleeding complications. The unadjusted 90-day mortality was 9.4% vs. 1.0% in the bleeding group vs. no bleeding group, respectively. After matching, the odds ratio (OR) for 90-day mortality in the bleeding group compared with the no bleeding group was 3.66 [95% confidence interval (CI): 2.17-6.17]. Long term overall survival was lower among patients in the bleeding group, adjusted hazard ratio (95% CI) for all-cause mortality was 1.47 (1.29-1.69). Postoperative complications were more common in the bleeding group (OR: 3.00, 95% CI: 2.38-3.79), including infections (OR: 2.80, 95% CI: 1.86-4.20). Bleeding complications were more frequent during the first third of the study time period as compared to the last third (P<0.001).ConclusionsPatients with bleeding complications had reduced long-term survival and higher incidence of postoperative complications. A declining trend in bleeding rates over time was noted.
| S-EPMC11320260 | biostudies-literature
Project description:IntroductionThe kidney transplant recipient population in the United States is aging rapidly, which may exacerbate some of the limitations of conventional outcome metrics.MethodsUsing data from the Scientific Registry of Transplant Recipients (SRTR), age-stratified unadjusted Kaplan-Meier and competing risk survival analyses were performed on a cohort of 238,123 adult recipients of a first-time single kidney transplant between 2000 and 2017. These were compared with a multistate model incorporating 5 post-transplant states (alive with functioning graft, death with functioning graft, graft failed (alive), retransplanted, and death after graft failure).ResultsKaplan-Meier resulted in an age-dependent overestimation of the risks of graft failure and death with functioning graft, compared with competing risk or multistate models. In elderly (≥75 years old) recipients, the absolute overestimation of the risk of death with functioning graft was 4-fold higher than in those younger than 55 years. The multistate model demonstrated that for patients transplanted at age 55 years and older, the probability of being back on dialysis was never more than 4% at any point post-transplant. The underlying reasons were low graft failure rates and high mortality after resuming dialysis as follows: 2-year mortality after graft failure was 38%, 54%, and 67% in recipients aged from 55 to 64 years, from 65 to 74 years, and those aged 75 years and older, versus 20% in those younger than 55 years.ConclusionMultistate models provide an accurate and comprehensive assessment of the life course of kidney transplant recipients. This may be particularly relevant in older recipients, who are more prone to event rate overestimation and for whom outcomes after graft failure are substantially worse than for younger recipients.
| S-EPMC9751842 | biostudies-literature