Post-transplant Year Research Articles

Influence of Bronchoscopic Interventions on Graft Function of Double Lung Transplant Recipients due to Cystic Fibrosis

Healing of bronchial anastomoses may sometimes be complicated and require bronchoscopic intervention (BI). The main aim of the study was to assess whether patients who require BI present comparable lung function after reaching 1-year posttransplant survival to those who did not require any BI by means of spirometry and 6-minute walk test (6MWT). This retrospective study included an analysis of 44 primary double lung transplant recipients who underwent transplant for end-stage respiratory failure in the course of cystic fibrosis transplanted in a single center between 2018 and 2021. Bronchoscopic intervention is defined as performing endoscopic bronchoplasty through balloon dilatation, cryoprobe, argon plasma, and/or laser treatment. Group 1 (25 patients who required at least 1 BI) presented similar spirometry parameters at qualification as group 2 (no BI). Statistically significant differences between the groups for the following parameters were reported: forced expiratory volume in 1 second (FEV1), FEV1 (%), Tiffeneau-Pinelli index (FEV1/forced vital capacity percentage of predicted value), oxygen saturation after conclusion of 6MWT (%) and oxygen saturation before 6MWT (%). In each case, the mean for the BI group in the first year was lower. All patients in this group received an average amount of 6.8 ± 4.9 bronchoscopic procedures during the first year (minimum=1; maximum=18). Strong negative correlations were observed between the number of balloons in the first year and the FEV1 (%) and FEV1/forced vital capacity percentage of predicted value indicators after the first year. Lung transplant recipients who underwent transplant because of cystic fibrosis and required at least 1 BI during the first posttransplant year presented inferior spirometry and 6MWT results in comparison with those who did not require any.

Antifungal Prophylaxis and Treatment Among Lung Transplant Recipients in Early Postoperative Stage: A Single-Center Study

Lung transplantation remains the only feasible option for certain patients with end-stage lung disease. Lifelong immunosuppression increases the risk of infection, including fungal infections. The aim of this study was to assess the effect of antifungal prophylaxis and treatment among lung transplant recipients in the early postoperative stage. This retrospective analysis included 127 patients who underwent lung transplantation between 2014 and 2021 in the lung transplant ward, 65.35% of whom were males. The most common indication for lung transplantation was cystic fibrosis (n=59; 46.46%). All of the patients were receiving inhaled amphotericin B. Within this group there were patients who also were treated with intravenous caspofungin, intravenous/oral voriconazole, or both. The difference in the efficacy against Candida spp. between caspofungin and voriconazole in the early post-transplant period was not statistically significant (χ2=0.5, P=.477). Moreover, the difference in the efficacy against Candida spp. between itraconazole and voriconazole during the first post-transplant year was not statistically significant (χ2=0.46, P=.496). Caspofungin and voriconazole are proper and relatively efficient antifungal prophylaxis and treatment options after lung transplantation. There was no significant difference between voriconazole and caspofungin as antifungal agents used in the early post-transplant stage. There was no significant difference between voriconazole and itraconazole as antifungal agents used during the first post-transplant year. Further research on this issue is required.

Restrictive Rather Than Routine Use Of Basiliximab For Heart Transplant Induction

Introduction The use of immunosuppression induction strategies greatly varies between heart transplant (HT) centers. Clinicians must weigh the risk of allograft rejection with infection and malignancies. Our center stopped routine induction with the Interleukin-2 receptor antagonist basiliximab in 2016 after findings of increased infection, malignancy, and a trend towards higher mortality. Hypothesis We aimed to assess the effect of our protocol change abandoning routine use of basiliximab on survival, allograft rejection, infection, and malignancy. Methods Retrospective single-center analysis of consecutive HT recipients from 2003 to 2015 and 2017-2019. In 2016 the induction protocol was changed, and the adjustment period was excluded. Furthermore, patients bridged to transplant with LVAD, re-transplantation and multi-organ transplants were not included. Results : A total of 398 patients were identified (mean age 55±11, 72% male) and grouped by induction with basiliximab or no induction. There were no clinically significant differences in baseline characteristics between the groups including age, panel reactive antibody % (PRA) and kidney function (Table). One-year mortality was significantly lower in the no-basiliximab group 1.9 vs 6.75% p 0.03 (Figure 1). Multivariate regression for basiliximab, PRA, age, gender, diabetes mellitus, creatinine did not identify independent risk factors for mortality. Significantly more patients in the no-basiliximab group had ≥ 1 rejection (≥ 2R ISHLT 2004) 68 vs 44% with significantly lower rejection free survival (p 0.0001) per log-rank test (Figure 2). There was no longer a significant difference in rates of bacterial and fungal infections as well as CMV-viremia and malignancies during the first-year post-transplant year. Conclusion Restrictive rather than routine use of basiliximab induction is no longer associated with increased infectious and early malignancy but remains associated with inferior survival despite lower incidence of early rejection and comparable immunological risk based on PRA. In the future improved individual immunologic risk profiling might be helpful to better risk stratify transplant candidates, who might benefit from induction. The use of immunosuppression induction strategies greatly varies between heart transplant (HT) centers. Clinicians must weigh the risk of allograft rejection with infection and malignancies. Our center stopped routine induction with the Interleukin-2 receptor antagonist basiliximab in 2016 after findings of increased infection, malignancy, and a trend towards higher mortality. We aimed to assess the effect of our protocol change abandoning routine use of basiliximab on survival, allograft rejection, infection, and malignancy. Retrospective single-center analysis of consecutive HT recipients from 2003 to 2015 and 2017-2019. In 2016 the induction protocol was changed, and the adjustment period was excluded. Furthermore, patients bridged to transplant with LVAD, re-transplantation and multi-organ transplants were not included. : A total of 398 patients were identified (mean age 55±11, 72% male) and grouped by induction with basiliximab or no induction. There were no clinically significant differences in baseline characteristics between the groups including age, panel reactive antibody % (PRA) and kidney function (Table). One-year mortality was significantly lower in the no-basiliximab group 1.9 vs 6.75% p 0.03 (Figure 1). Multivariate regression for basiliximab, PRA, age, gender, diabetes mellitus, creatinine did not identify independent risk factors for mortality. Significantly more patients in the no-basiliximab group had ≥ 1 rejection (≥ 2R ISHLT 2004) 68 vs 44% with significantly lower rejection free survival (p 0.0001) per log-rank test (Figure 2). There was no longer a significant difference in rates of bacterial and fungal infections as well as CMV-viremia and malignancies during the first-year post-transplant year. Restrictive rather than routine use of basiliximab induction is no longer associated with increased infectious and early malignancy but remains associated with inferior survival despite lower incidence of early rejection and comparable immunological risk based on PRA. In the future improved individual immunologic risk profiling might be helpful to better risk stratify transplant candidates, who might benefit from induction.

Prognostic Significance of Early Leukopenia in Heart Transplant Recipients

<h3>Purpose</h3> Although leukopenia is a relatively frequent finding after heart transplantation, its effects on patient outcomes remain poorly defined. We evaluated the long-term prognostic impact of early leukopenia in this patient population. <h3>Methods</h3> We performed a retrospective single-center cohort study in 133 consecutive heart transplant recipients transplanted between January 2009 and September 2016. Recipients with intensified immunosuppression (IS) and patients who died within the first post-transplant year were excluded. All patients received immunoinduction with basiliximab and maintenence IS therapy with tacrolimus (TAC)/mycophenolate mofetil (MMF)/steroids. Infection prophylaxis consisted of posaconasole (6 months), TMP-SMX (life-long) and valgancyclovir (discontinued pending positive Quantiferon-CMV assay). Early leukopenia was defined as any episode of WBC count <4.0x10⁹/L within 12 months after transplantation. Late CMV reactivation was defined as PCR CMV >1000 IU/mL after discontinuation of virostatic therapy. All patients were followed for 5 years. <h3>Results</h3> Within the first post-transplant year, 47 (35%) patients had at least one episode of leukopenia (Group A) and in 86 (65%) no leukopenia was registered (Group B). The two groups did not differ in gender (male; 77% in Group A vs. 86% in Group B, P=0.12), age (57±10 years vs. 54±11 years, P=0.25), heart failure etiology (ischemic: 41% vs. 42%, P=0.97), the presence of hypertension (68% vs. 61%; P=0.34) and diabetes (32% vs. 24%; P=0.23). IS regimen was comparable in both groups and consisted of TAC (mean C0 level 7.4±1.7 μg/mL vs. 7.2±2.1 μg/mL, P=0.41), MMF (mean dose 1979±100 mg vs. 1994±53 mg, P=0.11) and steroids. However, the duration of valgancyclovir therapy was significantly longer in Group A than in Group B (73±143 days vs. 46±97 days, P=0.001). During follow-up, the patients in Group A were more likely to develop malignancy (21% vs. 6% in Group B, P=0.01). We found no differences in late CMV reactivation (12% in Group A vs. 13% in Group B, P=0.98) and 5-year survival (90% vs. 91%; P=0.88) between the two groups. <h3>Conclusion</h3> In heart transplant recipients early leukopenia episodes are likely related to the prolonged use of virostatic therapy and may be associated with increased rates of post-transplant malignancies.

Performance of Donor-Derived Cell-Free DNA (dd-cfDNA) for Discriminating Acute Lung Allograft Injury in a Multicenter Cohort

Purpose Histological patterns of acute allograft injury including perivascular acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP) and acute lung injury (ALI) are frequent after lung transplant and have been associated with worse outcomes. Circulating dd-cfDNA has been proposed as a biomarker to discriminate acute allograft injury in lung recipients. We sought to determine the performance characteristics of three plasma dd-cfDNA thresholds for distinguishing acute lung allograft injury in a prospective, multicenter cohort. Methods The cohort was drawn from the Clinical Trials in Organ Transplantation-20 study and comprised 126 first adult lung recipients with 320 plasma samples that paired with a lung biopsy performed early within the first posttransplant year. Total cfDNA was isolated from ∼1mL of plasma using automated nucleic acid purification and the dd-cfDNA fraction determined at CareDx using next generation sequencing and validated bioinformatics. Biopsies were binned into typical sampling timeframes of 1, 3, and 6 months posttransplant. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for discriminating between a biopsy with vs. without acute allograft injury (defined as any of AR, LB, OP or ALI) was estimated at each timeframe for each of the following dd-cfDNA thresholds; 0.5%, 0.85%, and 1.0%. Results The Table reports the performance characteristics of each dd-cfDNA threshold at each early posttransplant timeframe. At 1month posttransplant the NPV, indicating the probability of a biopsy without acute allograft injury having a concurrent plasma dd-cfDNA value below the threshold, was poor for all evaluated thresholds. However, by 6months posttransplant the NPV improved, in particular for the 0.5% threshold. Conclusion In this prospective real-world cohort, a dd-cfDNA threshold of 0.5% achieved a high NPV for acute histological allograft injury at 6 months posttransplant. Histological patterns of acute allograft injury including perivascular acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP) and acute lung injury (ALI) are frequent after lung transplant and have been associated with worse outcomes. Circulating dd-cfDNA has been proposed as a biomarker to discriminate acute allograft injury in lung recipients. We sought to determine the performance characteristics of three plasma dd-cfDNA thresholds for distinguishing acute lung allograft injury in a prospective, multicenter cohort. The cohort was drawn from the Clinical Trials in Organ Transplantation-20 study and comprised 126 first adult lung recipients with 320 plasma samples that paired with a lung biopsy performed early within the first posttransplant year. Total cfDNA was isolated from ∼1mL of plasma using automated nucleic acid purification and the dd-cfDNA fraction determined at CareDx using next generation sequencing and validated bioinformatics. Biopsies were binned into typical sampling timeframes of 1, 3, and 6 months posttransplant. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for discriminating between a biopsy with vs. without acute allograft injury (defined as any of AR, LB, OP or ALI) was estimated at each timeframe for each of the following dd-cfDNA thresholds; 0.5%, 0.85%, and 1.0%. The Table reports the performance characteristics of each dd-cfDNA threshold at each early posttransplant timeframe. At 1month posttransplant the NPV, indicating the probability of a biopsy without acute allograft injury having a concurrent plasma dd-cfDNA value below the threshold, was poor for all evaluated thresholds. However, by 6months posttransplant the NPV improved, in particular for the 0.5% threshold. In this prospective real-world cohort, a dd-cfDNA threshold of 0.5% achieved a high NPV for acute histological allograft injury at 6 months posttransplant.

High Volume Centers Have Lower Incidence of Acute Cellular Rejection in Pediatric Lung Transplant Recipients and Better Survival After Treatment

Purpose Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. Methods The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). Results 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). Conclusion ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR. Acute cellular rejection (ACR) is a common form of allograft rejection in pediatric recipients after lung transplant (LTx). ACR most commonly occurs during the 1st post-transplant year. This study sought to determine if transplant center volume affected ACR-related outcomes in children after LTx. The United Network for Organ Sharing (UNOS) Registry was queried for patients <18 years who underwent LTx in 1987-2020. Cohorts were patients who were treated for ACR during the 1st post-LTx year (ACR group) and who did not experience ACR (non-ACR). Survival of patients who had ACR was compared by LTx center volume defined as average of LTx/year: >5LTx/year (high), >1-≤5LTx/year (medium) and 1LTx/year (low). 1338 patients were included in our analysis with 271 (20.3%) identified as having ACR. Compared to non-ACR, the ACR cohort were older (median 14 [11-16] vs 13 [7-16] years, p<0.001), more commonly female (65.3% vs 57.3%, p=0.016), more commonly diagnosed with cystic fibrosis (62.3% vs 45.5%, p<0.001), and had a higher lung allocation score at LTx (37.3 [34.6-47.8] vs 35.8 [33-42.6], p=0.029). Kaplan-Meier survival of ACR vs non-ACR cohorts trended towards lower survival at 5-yr (37% vs 47%) & 10-yr (25% vs 34%) post-LTx, p=0.06. ACR occurred in 17% of patients at high (n=98/574), 18.5% (n=73/395) at medium, and 27% (n=100/369) at low volume centers. Patients treated for ACR at high volume centers had better post-transplant survival than low volume centers (p<0.001) but similar survival to those at medium volume centers (p=0.081; Figure). No significant difference in survival was observed in medium vs low volume centers (p=0.14). ACR treated within the 1st post-LTx year influences survival of pediatric LTx recipients. ACR incidence was lowest at higher volume centers where post-ACR treatment survival outcomes were also superior. More analysis is needed to determine factors affecting differences in center outcomes regarding ACR.

Racial and Socioeconomic Disparities in Pediatric Heart Transplant Outcomes in the Era of Anti-Thymocyte Globulin Induction

<h3>Purpose</h3> A recent multicenter pediatric study using antithymocyte globulin (ATG) induction found a reduced risk of first yr rejection in Black heart transplant (tx) recipients. We investigated this finding in the broader field and studied the effects of race and socioeconomic disparity on outcomes in ATG-induced children. <h3>Methods</h3> Using the Pediatric Heart Transplant Society registry, we compared outcomes in Black and White children 1-17 yrs old who underwent heart tx with ATG induction between 2000-2020. The primary outcomes of treated rejection, rejection with hemodynamic compromise (HC), and graft loss (death or re-transplant) were studied over 1- and 10-yr time intervals as well as late outcomes conditional on 1-yr survival<i>.</i> We explored the association of these outcomes with race and socioeconomic disparity, assessed using neighborhood deprivation index [NDI] score at 1-yr post-tx (high NDI score implies more socioeconomic disadvantage). <h3>Results</h3> The study cohort included 1719 ATG-induced pediatric heart tx recipients (23% Black, 77% White). There was no racial difference in incidence of first yr treated rejection (Black 24.5%, White 28.1%, p = 0.2). During the 10 yr follow up, the risk of treated rejection was similar between Black and White recipients; however, Black recipients were at higher risk of HC rejection (p = 0.009) and graft loss (p = 0.02, log rank test). Black recipients had a higher mean NDI score (0.43 vs 0.36, p < 0.001). A higher risk of graft loss was associated with high NDI score in both White and Black recipients (p < 0.001, Fig). In a multivariable Cox model, both high NDI score (HR 2.03, 95% CI 1.38-2.98) and Black race (HR 1.99, 95% CI 1.36-2.93) were associated with graft loss. <h3>Conclusion</h3> Black race and socioeconomic disadvantage remain associated with HC rejection and graft loss after the first post-transplant year in pediatric heart tx patients with ATG induction. These disparities represent important opportunities to improve long term tx outcomes in children.

A Positive CDC T-cell Crossmatch is Strongly Associated with Allograft Loss and Early Rejection in Pediatric Heart Transplant Recipients

<h3>Purpose</h3> A recent multi-center study (CTOT-04) reported similar first year outcomes in children with CDC T-cell crossmatch (XM) + and XM- heart transplant (HT) but was underpowered and had only 11 children in the CDC+ HT group. We assessed the association of donor specific T-cell CDC and Flow XM HT with the risk of rejection and allograft loss in US pediatric recipients over 20 years. <h3>Methods</h3> We queried the OPTN database for all pediatric HT performed between 1999 and 2019. Donor specific T-cell XM results were categorized as CDC+, Flow+/CDC Unknown, Flow+/CDC-, and Flow-. Covariate adjustment using a propensity score balanced risk factors between the XM+ and XM- groups. <h3>Results</h3> Of 4695 pediatric HT, there were 165 CDC+, 288 Flow+/CDC Unknown, 94 Flow+/CDC-, and 4148 Flow- recipients. The median age at HT was 7 years, 44% female, 55% white, and 44% had a pre-HT diagnosis of CHD. Pre-HT diagnosis, hemodynamic support, and year of heart transplant differed between the XM+ and XM- groups prior to propensity score adjustment. After adjusting for propensity score, children with a CDC+ HT were significantly more likely to lose their allograft or develop rejection requiring treatment in the first post-HT year (<b>Table</b>). Propensity score matching and stratification by propensity score quintile demonstrated similar results. Over the period of the study, there was a significant shift in the type of XM assays performed (1999: 90% of HT with CDC XM, 32% Flow XM; 2019: 28% of HT with CDC XM, 87% Flow XM). <h3>Conclusion</h3> Children receiving a CDC+ XM HT are at higher risk of graft loss and rejection during the first post-transplant year, suggesting higher anti-HLA antibody burden in such recipients. The lack of differences in allograft loss and rejection with a positive Flow XM alone may be due to current treatment strategies. The shift away from performing a CDC XM results in a loss of important prognostic information. Prospective clinical trials of donor acceptance and antibody treatment strategies are needed.

Association of Chronic Proton Pump Inhibitor Use in Lung Transplant Recipients with Long-Term Outcomes: A Retrospective Cohort Study

<h3>Purpose</h3> Proton pump inhibitors (PPI) are widely prescribed long-term for lung transplant recipients in the absence of proven PPI-indicated conditions, despite little evidence supporting this practice. Several adverse effects related to chronic PPI use have been reported in observational studies in the general population. We aimed to assess whether chronic PPI use in lung transplant recipients is associated with benefits in long-term outcomes, specifically chronic lung allograft dysfunction (CLAD) and death/retransplant. <h3>Methods</h3> All adult lung transplant recipients transplanted between 1999 and 2018 who survived past 1-year post-transplant and had at least 4 pulmonary function tests were included. Patients were classified as on-PPI if there was a recorded prescription in the electronic medical record for dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole before 1-year post-transplant that continued after 1-year post-transplant. All other patients were classified as off-PPI. Cox proportional hazards models were used to determine the associations between PPI use and outcomes. <h3>Results</h3> 171 patients were off-PPI and 1394 patients were on-PPI. 780 patients developed CLAD and 808 died/were retransplanted. Compared to the on-PPI group, the off-PPI group was younger, had fewer re-transplants, and more transplants before 2010. In univariable analyses, PPI use was protective against CLAD (HR=0.76[0.62-0.94], p=0.01) and death/retransplant (HR=0.82[0.67-0.99], p=0.04). These associations were no longer significant after adjusting for age, sex, transplant type, transplant number, transplant era, primary disease, and CMV mismatch in multivariable analyses for CLAD (HR=0.87[0.70-1.08], p=0.20) and death/retransplant (HR=0.83[0.68-1.02], p=0.07). <h3>Conclusion</h3> In a retrospective cohort study, chronic PPI use after the first post-transplant year in lung transplant recipients was associated with a non-statistically significant benefit in death/retransplant, independent of potential confounders. As additional unknown confounders may exist, prospective randomized studies are needed to provide higher levels of evidence. Nevertheless, it may be reasonable to re-evaluate the practice of widely prescribing long-term PPIs in lung transplant recipients lacking a clear indication.

SARS-CoV-2 T-Cell Responses in Allogeneic Hematopoietic Stem Cell Recipients following Two Doses of BNT162b2 mRNA Vaccine.

Background: At variance to humoral responses, cellular immunity after anti-SARS-CoV-2 vaccines has been poorly explored in recipients of allogeneic hematopoietic stem-cell transplantation (Allo-HSCT), especially within the first post-transplant years where immunosuppression is more profound and harmful. Methods: SARS-CoV-2 Spike protein-specific T-cell responses were explored after two doses of BNT162b2 mRNA vaccine in 45 Allo-HSCT recipients with a median time from transplant of less than 2 years by using INF-γ ELISPOT assay and flow-cytometry enumeration of CD4+ and CD8+ T lymphocytes with intracellular cytokine production of IFN-γ and TNF-α. Results: A strong TNF-α+ response from SARS-CoV-2-specific CD4+ T-cells was detected in a majority of humoral responders (89%) as well as in a consistent population of non-humoral responders (40%). Conclusions: T-cells are likely to participate in protection against COVID-19 viral infection, even in the absence of detectable antibody response, especially in the first years post-transplant in Allo-HSCT recipients.

Natural History of Bone Disease following Kidney Transplantation.

Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year. We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism. Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip. Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients. Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.

Early prediction of renal graft function: Analysis of a multi-center, multi-level data set

Purpose of the studyLong-term graft survival rates after renal transplantation are still poor. We aimed to build an early predictor of an established long-term outcomes marker, the estimated glomerular filtration rate (eGFR) one year post-transplant (eGFR-1y). Materials and MethodsA large cohort of 376 patients was characterized for a multi-level bio-marker panel including gene expression, cytokines, metabolomics and antibody reactivity profiles. Almost one thousand samples from the pre-transplant and early post-transplant period were analysed and employed for machine learning-assisted prediction. ResultsPre-transplant data led to a prediction achieving a Pearson's correlation coefficient of r=0.38 between measured and predicted eGFR-1y. Two weeks post-transplant, the correlation was improved to r=0.63, and at the third month, to r=0.76. eGFR values were stable throughout the first post-transplant year. Several characteristics were predictive for eGFR, including age of donor and recipient, body mass index, HLA mismatch, cytomegalovirus mismatch and valganciclovir prophylaxis. Additionally, a subset of 19 nuclear magnetic resonance bins of the urine metabolome data was shown to have potential applications in non-invasive eGFR monitoring. Importantly, we identified the expression of the genes TMEM176B and HMMR as potential prognostic markers for changes in the eGFR after the second post-transplantation week. ConclusionsOur multi-center, multi-level data set represents a milestone in the efforts to predict transplant outcome. While an acceptable predictive capacity was achieved, we are still far from predicting changes in the eGFR precisely. Additional studies employing further marker panels are needed to establish predictors of eGFR-1y for clinical application; herein, gene expression markers seem to hold the most promise.

Galectin-3 as an independent prognostic factor after heart transplantation.

Galectin-3 (GAL3) is linked to the prognosis of patients with heart failure and after heart transplantation (HTx). We assessed the prognostic role of GAL3 in a long-term follow-up after HTx. HTx patients (N=121) were evaluated in a single-center, noninterventional, prospective, observational study. The median follow-up was 96 months (2942 days, interquartile range (IQR) 2408-3264 days), and 40 patients died. GAL3 was measured before HTx, +10 days after HTx, and during the first posttransplant year. Survival analysis (all-cause mortality) was performed with adjustments for clinical and laboratory variables. The median pretransplant GAL3 level was 18.0μg/L (IQR 14.0-25.9), and higher values were associated with older age, worse kidney function, left ventricular assist device use before HTx, a higher IMPACT score, and mortality. Increased pretransplant GAL3 predicted shorter survival time (HR 2.05, 95% CI 1.09-3.85, p<.05). Similar prognostic power had GAL3 on the 10th posttransplant day (HR 2.03, 95% CI 1.08-3.82, p<.05). GAL3 was an independent predictor of death after adjustment for clinical variables (age, infection, diabetes, smoking, IMPACT score, and troponin). GAL3 was significantly associated with all-cause mortality after adjusting for clinical and laboratory variables and may serve as an additional prognostic biomarker.

Induction Therapy and Therapeutic Antibodies.

Prevention of allograft rejection is one of the crucial goals in solid organ transplantation to ensure durability of the graft and is chiefly mediated by cellular and humoral pathways targeting cell surface alloantigens. The risk of rejection is highest in the first post-transplant year and wanes with time albeit the risk always exists and varies with the type of organ transplanted. Induction therapies refer to the use of high-intensity immunosuppression in the immediate post-operative period to mitigate the highest risk of rejection. This term encompasses chiefly the use of antibody therapies directed against one of the key pathways in T-cell activation or abrogating effects of circulating alloantibodies. These antibodies carry more potent immunomodulatory effect than maintenance immunosuppressive therapy alone and many of them lead to durable immune cell depletion. A variety of monoclonal and polyclonal antibodies have been utilized for use not only for induction therapy, but also for treatment of allograft rejection when it occurs and as components of desensitization therapy before and after transplantation to modulate circulating alloantibodies.

937. A Clinical Prediction Tool to Determine Risk of Infection in the First Year Following Heart Transplant

BackgroundInvasive infection is a dangerous complication of heart transplant (HT). No objectively-defined set of risk factors has been established which can reliably predict infection in this population. The aim of this study was to develop a clinical prediction model for use at one month post-HT with the ability to predict serious infection in the first year.MethodsA retrospective cohort study of all HT recipients at a single center between 2000 and 2018 was performed, excluding dual-organ recipients, those who died within one month of HT, and those with insufficient data. The composite endpoint included cytomegalovirus infection (CMV), herpes simplex (HSV) or varicella zoster virus infection (VZV), blood stream infection (BSI), and invasive fungal infection (IFI). The follow-up period extended from 1 month to 1 year post-HT. A least absolute shrinkage and selection operator (LASSO) regression model was fit using 13 candidate variables. A C-statistic, calibration curve, and Brier score were used to assess model performance.Results375 patients were analyzed; 93 outcomes occurred (65 CMV, 3 HSV, 2 VZV, 28 BSI, and 15 IFI). 12 of 13 variables remained in the final model: year of transplant, age at transplant, ischemic cardiomyopathy, diabetes, immune-mediating disease, need for renal replacement therapy in first month, CMV risk status (high, intermediate, low) derived from donor-recipient serology, use of basiliximab induction, use of cytolytic agent in first month, use of ritixumab in first month, rejection treated with high-dose steroids in first month, lymphocyte count under 0.75 x103cells/µL at 1 month, and inpatient status at 1 month. The C-statistic was 0.82 and Brier score 0.142. The calibration curve is shown in Figure 1. Figure 1. Calibration plot Actual versus predicted probability of infection by 1 year. Gray line = ideal Dotted line = smoothed non-parametric calibration curveConclusionThis model synthesizes multiple highly-relevant clinical and laboratory parameters, available at 1 month post-HT, into a unified, objective, and clinically-useful prediction tool for the occurrence of serious infection in the first post-transplant year. Good discrimination and calibration are demonstrated. External validation is required before generalized use.Disclosures Jennifer Chow, M.D., M.S., Merck (Grant/Research Support)Takeda (Grant/Research Support) David R. Snydman, MD, Merck (Consultant, Advisor or Review Panel member, Research Grant or Support)Takeda (Shire) (Advisor or Review Panel member)

Rare Malignant Indications for Liver Transplantation: A Collaborative Transplant Study Report.

Introduction: Hepatocellular carcinoma (HCC) is by far the leading malignant indication for liver transplantation (LT). Few other malignancies, including cholangiocellular carcinoma (CCC), metastases from neuroendocrine tumors (NET), and sarcomas of the liver (LSAR), also are commonly accepted indications for LT. However, there is limited information on their outcome after LT.Methods: Graft and patient survival in 14,623 LTs performed in patients with hepatocellular carcinoma, CCC, NET, and LSAR from 1988 to 2017 and reported to the Collaborative Transplant Study were analyzed.Results: The study group consisted of 13,862 patients who had HCC (94.8%), 498 (3.4%) who had CCC, 100 (0.7%) who had NET, and 163 (1.1%) who had LSAR. CCC patients showed a 5-year graft survival rate of 32.1%, strikingly lower than the 63.2% rate in HCC, 51.6% rate in NET, and 64.5% rate in LSAR patients (P < 0.001 for all vs. CCC). Multivariable Cox regression analysis revealed a significantly higher risk of graft loss and death due to cancer during the first five post-transplant years in CCC vs. HCC patients (HR 1.77 and 2.56; P < 0.001 for both). The same risks were increased also in NET and LSAR patients but did not reach statistical significance.Conclusion: Among patients with rare malignant indications for LT, CCC patients showed significantly impaired graft as well as patient survival compared to HCC patients. The observed differences might challenge traditional decision-making processes for LT indication and palliative treatment in specific hepatic malignancies.

The economic burden of NIPC and BOS following allogeneic HSCT in patients with commercial insurance in the United States

AbstractNoninfectious pulmonary complications (NIPC) after allogeneic hematopoietic stem cell transplantation (alloHSCT), including bronchiolitis obliterans syndrome (BOS), cause significant morbidity and mortality, but their impact on health care resource utilization (HRU) and costs is unknown. This longitudinal retrospective study quantified the economic burden of NIPC and BOS in alloHSCT patients using commercial claims data from the IQVIA PharMetrics Plus database. Study patients were aged 0 to 64 years and underwent alloHSCT between 1 January 2006 and 30 September 2018, and were observable 12 months before and up to 5 years after index alloHSCT. NIPC patients were identified using International Classification of Disease (ICD) diagnosis codes. Outcomes were mean per patient HRU (inpatient admissions, outpatient office, hospital visits, and prescription medications) and costs paid by insurers in each post-transplant year. Among 2162 alloHSCT patients, 254 developed NIPCs, and 155 were propensity score (PS)-matched to non-NIPC patients. The year following transplantation, NIPC patients had significantly higher inpatient admission rates (3.8 ± 3.2 vs non-NIPC: 2.6 ± 2.4; P < .001) and higher total costs ($567 870 vs $412 400; P = .07), reflecting higher costs for inpatient admissions ($452 475 vs $300 202; P = .06). Among those observable for more years, costs remained higher for NIPC patients, reflecting significantly higher inpatient admission rates in the first 3 years following transplant. Subanalysis of patients with diagnoses likely reflective of BOS were consistent with these findings. AlloHSCT patients who developed NIPC had higher health care resource utilization and incurred higher costs compared with alloHSCT patients who did not develop NIPC following transplant.

Implementing a personalized pharmaceutical plan in kidney or liver transplant patients: study protocol for a stepped-wedge cluster randomized trial (GRePH)

BackgroundNowadays, the main challenge of transplantation is the improvement of long-term care, aiming at reducing treatment-related complications and at decreasing rejection rates. Patients’ adherence to both treatment and hygienic-dietary measures is mandatory to achieve these objectives. Adherence to immunosuppressive drugs is estimated to be only 70%. We hypothesized that the implementation of a personalized pharmaceutical plan (PPP) would increase adherence and therefore graft survival.Methods/designThis study is a stepped-wedge cluster randomized trial with transplantation units defining clusters. Twelve clusters from 10 university hospitals were recruited. All centres started on the same day in the control phase. Every 7 weeks, one centre will switch to the intervention phase and remain there until the end of inclusions. We plan to recruit 1716 kidney and/or liver transplant patients. The intervention phase consists in setting up the PPP: development of the patient’s hospital and community pharmaceutical follow-up. In the hospital, the pharmacist will carry out drug reconciliation upon admission, daily pharmaceutical follow-up of prescriptions and pharmaceutical interviews with the patient in order to explain the modalities of taking immunosuppressive drugs and hygienic-dietary measures. After hospitalization, during the post-transplantation year, pharmaceutical meetings will take place, prior to medical consultations in order to check the patient’s understanding of the prescription, his adherence, to remind them of hygienic-dietary measures and to look for adverse effects. The hospital pharmacist will also be in charge of establishing a close link with the community pharmacist (CP) and general practitioner, especially providing discharge medication reconciliation, an e-learning and a checklist. Moreover, prior to each pharmaceutical consultation, the hospital pharmacist will contact the CP to discuss patient adherence.The primary outcome is adherence to immunosuppressive treatments 1 year post-transplantation assessed by using the BAASIS questionnaire and the health insurance data from the national health data system. A medico-economic study will measure the efficiency of this plan.DiscussionGRePH aims to increase adherence of liver and/or kidney transplant patients to their immunosuppressive therapies in order to reduce transplant rejections. To this end, a new clinical pharmacy model, the PPP, will be set up in 10 university hospitals.Trial registrationClinicalTrials.gov NCT04295928. Registered on 5 March 2020

Dialysis Nonadherence and Kidney Transplant Outcomes: A Retrospective Cohort Study

Concerns about nonadherent behaviors often prevent dialysis patients from entering waitlists for transplant even though there is an inconsistent association of these behaviors with posttransplant outcomes. We examined the association between plausible metrics of nonadherence related to dialysis treatment and posttransplant outcomes. Retrospective cohort. We linked national dialysis treatment data with transplant registry data. Adult patients receiving maintenance hemodialysis from January 1, 2004, through December 31, 2014, who received a kidney transplant at a US center. We examined 5 nonadherence metrics: serum potassium level (≥5.2 mEq/L), serum phosphorus level (>5.5 mg/dL), interdialyticweight gain (IDWG;≥5 L), shortened treatments (≥30 min), and missed treatments (≥1); missed treatment data were available only for 2004-2009. These metrics were characterized per proportion of time under observation. Dialysis observation time was divided into 3-month intervals (quarters), and the number of nonadherent measurements in each domain was calculated for each quarter. Allograft loss, mortality, and acute rejection in the first posttransplant year. Using Cox proportional hazards and logistic regression, we estimated the hazard ratios for graft loss and mortality and odds ratios for rejection. 9,543 patients met inclusion criteria. In our primary model, hyperphosphatemia (adjusted hazard ratio [aHR], 1.27 [95% CI, 1.08-1.49]), large IDWG (aHR, 1.39 [95% CI, 1.23-1.59]), and shortened treatments (aHR, 1.54 [95% CI, 1.12-2.13]) were associated with greater rates of allograft loss, but hyperkalemia was not. Large IDWG (aHR, 1.49 [95% CI, 1.29-1.73]) and shortened treatments (aHR, 1.34 [95% CI, 1.13-1.58]) were associated with mortality, whereas hyperkalemia and hyperphosphatemia were not. Only shortened treatments were associated with an increased risk of acute rejection (adjusted odds ratio, 3.88 [95% CI, 1.98-7.58]). In models limited to the years 2004-2009 that included missed treatments, missed treatments were associated only with mortality. Unmeasured confounding (eg, dietary data); adherence metrics used may have multiple, complex causes. Plausible measures of dialysis nonadherence have long-term associations with allograft and patient survival. Behavioral metrics were more closely associated with outcomes than laboratory markers were. The implications of nonadherent behaviors for dialysis patients must be carefully considered before patients are excluded from transplantation.

The Second Helsinki Face Transplantation and the World Experience of Revision Surgery During the First Posttransplantation Year.

We conducted a review of all surgical interventions performed during the first postoperative year in published face transplantation (FT) cases. In addition, we herein present our second FT patient, a full-face composite FT with an emphasis on surgical revisions after transplantation. A literature review was conducted and resulted in 376 publications of which 33 included reference to surgical interventions during the first post-FT year. For our second FT patient, a thorough review of all medical records was performed. Among the first 41 FTs, 32 FT patients had reports with reference to corrective surgery during the first year (22 composite and 10 soft-tissue FTs). Soft-tissue FTs had a median of 2 procedures (range, 1-8 procedures), and composite FTs, 3 procedures per patient (range, 1-9 procedures). Nearly all early interventions (<1 month) were performed in composite FT patients (anastomotic occlusion, hematoma, sialocele, palatinal dehiscence). The most common late interventions were scar corrections, tissue suspensions, periorbital corrections, osseal and dental procedures, and interventions for palatinal dehiscence and sialocele. Our second FT patient has recovered well and has undergone 3 surgical interventions during the first year. Surgical interventions are very common during the first postoperative year after FT, and composite FTs are more prone to complications necessitating surgical intervention than soft-tissue FTs. There is a wide variety of complications reflecting the heterogeneity of FT allografts. Corrective surgery in FT patients appears safe with only a few reported complications.