Time Of LTx Research Articles

Long-Term Follow-Up of Patients with Primary Sclerosing Cholangitis Undergoing Liver Transplantation with Duct-to-Duct Biliary

Background Reconstruction of biliary drainage after liver transplantation (LTx) in patients with primary sclerosing cholangitis (PSC) has been a matter of controversy. Over the recent years, the traditional method of Roux-en-Y hepaticojejunostomy (RY) has been challenged by duct-to-duct (DD) biliary reconstruction. The argument against DD reconstruction has been for potential increased risk of development of cholangiocarcinoma (CCA) in the bile duct remnant. Methods This is a retrospective review of biliary complications, graft and patient survival after LTx in PSC patients based on type of biliary reconstruction DD vs. RY. Results A total of 120 LTx for PSC were performed between 2005 and 2016. Twenty two patients were excluded because they received partial grafts. DD was done in 39 patients and 59 patients were reconstructed with RY. One-, 5-, and 10-year survival was similar between the two groups. Bile leak and biliary stricture was not significantly different between the 2 groups. Nine patients in DD group (23%), and 13 patients in RY group developed biliary strictures and all managed endoscopically or percutaneously. There was one case of anastomotic leak in each group. There was no case of CCA observed in these patients over the long period of follow-up. Conclusion DD biliary reconstruction at the time of LTx in selected PSC patients is both effective and safe, with comparable outcomes with those with RY reconstruction and NO increased risk for development of CCA in the bile duct remnant.

Early outcomes of lung transplantation for bronchiolitis obliterans syndrome after allogeneic haematopoietic stem cell transplantation: a single-centre experience.

Bronchiolitis obliterans syndrome (BOS) is a serious late complication following allogeneic haematopoietic stem cell transplantation (allo-HSCT) and is associated with chronic graft-versus-host disease. However, the outcome of medical treatment for BOS, mainly immunosuppressive therapy, is disappointing. This study evaluated the early outcomes of lung transplantation (LTx) as a treatment option for severe BOS. Between January 2010 and December 2014, we retrospectively reviewed the medical records and postoperative outcomes of 9 patients who underwent LTx for BOS after allo-HSCT at a single institution. The median age of patients at the time of LTx was 21 years, and the median interval from the diagnosis of BOS to LTx was 17.1 months. At the time of LTx, 5 patients were receiving oxygen therapy via nasal prongs, whereas the remaining 4 were receiving mechanical ventilation supports, 2 of whom requiring extracorporeal lung support. All patients underwent bilateral lung transplantation. During a median follow-up of 17 months after LTx, 2 patients died: one of intra-cranial haemorrhage and pneumonia during hospitalization and another patient of pneumonia and septic shock after discharge. Although the follow-up was short, the remaining 7 patients are currently healthy and active except one who developed BOS 45.3 months after LTx; he is on the waiting list for retransplantation. One patient experienced acute rejection that resolved after steroid pulse therapy. There was no relapse of the haematological disease after LTx. LTx could be a reasonable therapeutic option in selected patients with refractory BOS not responsive to conventional therapy.

Tacrolimus Concentration/Dose Ratio is Associated with Renal Function After Liver Transplantation.

The calcineurin inhibitor (CNI) tacrolimus (Tac) is an effective immunosuppressant used after liver transplantation (LTx), but is often associated with CNI nephrotoxicity. Currently, there is no simple clinical predictor for CNI nephrotoxicity after LTx. We hypothesized that the Tac metabolism rate - defined as the blood concentration normalized by its daily dose (the C/D ratio) - is associated with post-LTx renal impairment. We analyzed the relationship between the C/D ratio and post-transplant renal function in 179 patients who underwent LTx between 2000 and 2012 and were initially immunosuppressed with Tac, mycophenolate mofetil, and prednisolone. Six months after LTx, 115 patients were categorized into 1 of 2 groups based on their Tac C/D ratio (<1.09 or ≥1.09): fast (n=58) or slow (n=57) metabolizers. The renal function was determined 36 months after LTx using the estimated glomerular filtration rate (eGFR) as described by Cockcroft and Gault. At the time of LTx there was no statistically significant difference between the eGFR of fast and slow metabolizers. Six months (P=0.016), 12 months (P=0.001), and 36 months (P=0.018) after LTx, fast Tac metabolizers had significantly more impaired renal function than slow metabolizers. Because of a presumption of CNI nephrotoxicity, 32.8% of fast metabolizers and 14.0% of slow metabolizers were switched from Tac to other immunosuppressants (P=0.027). In this study, the Tac metabolism rate appears to influence renal function after LTx, suggesting that a C/D ratio of <1.09 is associated with increased CNI nephrotoxicity in LTx recipients.

Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation.

The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

206 Bone quality at the time of lung transplant in cystic fibrosis patients

Background and Hypothesis As CF patients get older, morbidities such as CF-related bone disease (CFBD), superimpose on the pre-existing complications. CFBD predisposes to fractures, especially of the ribs and vertebrae. Knowing that bone mineral density (BMD) is a poor predictor of fractures in CF, we postulate that alterations in bone quality will likely contribute to their propensity to fracture. Methods In order to assess bone quality in CF patients, a 2 cm segment of rib was recovered during lung transplant (LTx). Controls consisted in similarly aged lung donors (D). Dual-energy X-ray absorptiometry (DXA), micro-CT, bone histomorphometry and microcrack detection were used to assess BMD, microarchitecture, bone remodeling and quality of bone respectively. Results Over 17 CF and 21 donor's specimens were analyzed. Patients were stratified according to bisphosphonate (BP) or steroid (GC) treatment at the time of LTx. Ex vivo rib BMD, trabecular BMD and bone volume determined by micro-CT as well as trabecular thickness were significantly reduced in CF, with patients on GC having the lowest values. Despite similar surface occupied by osteoblasts, osteoid parameters (volume, surface and thickness) were lower in CF, regardless of the use of GC or BP. Number of osteoclasts and eroded surfaces were comparable among the groups. Microcracks were 3 to 4 times higher in CF than in D. Of note, the highest microcrack density was found in patients on BP. Conclusion Our data suggest alterations in the bone quality of CF ribs as evidenced by a decrease in osteoblast function and bone formation resulting in the uncoupling of bone remodeling, and the accumulation of microdamages.

Survival in children on extracorporeal membrane oxygenation at the time of lung transplantation.

Limited data exist on ECMO at the time of LTx in children. The UNOS database was queried from 2000 to 2013 for pediatric lung transplant recipients (<18yr) to assess post-transplant survival of patients on ECMO at the time of LTx. Of 587 pediatric recipients with 17 on ECMO, 585 were used for univariate and Kaplan-Meier function analysis, 535 for multivariate Cox models, and 24 for propensity score matching. Univariate Cox (HR=1.777; 95% CI: 0.658, 4.803; p=0.257) and Kaplan-Meier function (log-rank test: chi-square (df=1): 1.32, p=0.250) analyses did not identify a survival difference between ECMO and non-ECMO, while multivariate Cox models (HR=1.821; 95% CI: 0.654, 5.065; p=0.251) did not demonstrate an increased risk for death. Propensity score matching analysis (HR=1.500; 95% CI: 0.251, 8.977; p=0.657) also failed to demonstrate a significantly increased hazard ratio. Using a contemporary cohort of pediatric lung transplant recipients, the use of ECMO at the time of lung transplantation did not negatively impact survival.

Pulsatile Perfusion and Delayed Renal Transplantation (Tx) for Combined Liver-Kidney Tx.

Background: Patients requiring combined liver and kidney transplantation (LKTx) are at risk for worse outcomes due to severity of illness and complexity of the procedure. Delayed function of the renal graft can result from hypotension and pressor use related to the LTx procedure. Delayed Tx of the kidney graft may allow post-LTx stabilization of hemodynamics and coagulopathy. Methods: 95 LKTx were performed between 2002-2012 at our center. All kidneys underwent continuous hypothermic pulsatile perfusion until Tx; 70 with simultaneous (at time of LTx, Gp1) and 25 with delayed Tx (Gp2, performed at a later time as a second operation). The median MELD score was 26. In each case, the kidney was transplanted through a separate Gibson incision in the left pelvis. All patients received continuous veno-venous hemodialysis during the LTx which was continued until KTx. Results: Recipient, donor and transplant characteristics were comparable in both groups. Mean liver cold ischemia time (CIT) was less than 7 hours in both groups, while kidney CIT was 10±3 (range 5-19) and 37±9 (range 20-53) hours, for Gp1 and Gp2 (p<0.001), respectively. The two study groups did not differ significantly for dialysis in the first 7 days, nor for urine output in the first 24 hours. GFR was higher for Gp2 at 6- and 12-months (73 vs 67 at 6 months and 73 vs 64 at 12 months) (p=ns). In Gp1, mean FFP and platelet transfusions were higher (p<0.01). In Gp2, at the time of KTx, 9 patients (36%) didn't require any blood product transfusion, and 15 (60%) required significantly less transfusion. In delayed approach (Gp2), of 11 patients who were on pressors post-LTx, 3 were off (27%) and 7 had decreased need for pressors (64%) at the time of KTx. Sub-group analyses in Gp2 (kidney CIT <36h [Gp2a, n=11], and >36h [Gp2b, n=14]) showed similar GFR, graft (kidney and liver) and patient survival rates at 1-year. Graft and patient survivals in Gp1 and Gp2 at 90-days and 1-year were equivalent. 3-year Cox regression survival for the kidney graft was equivalent (82%). Conclusion: In LKTx patients, KTx can be safely delayed up to 2 days post-LTx with outcomes comparable to simultaneous Tx. Delayed Tx of the kidney post-LTx allows time for stabilization of the patient and decrease in pressor needs (up to 90%), and creates flexibility for the management of patients and personnel at a high-volume transplant center.

Chronic kidney disease and associated mortality after liver transplantation – A time-dependent analysis using measured glomerular filtration rate

The accuracy of creatinine-based estimated GFR (eGFR) in assessing the prevalence of chronic kidney disease (CKD) and associated mortality after liver transplantation (LTx) is unknown. Using measured GFR (mGFR) by iothalamate clearance, we determined the prevalence of the entire spectrum of renal dysfunction and the impact of CKD on mortality after LTx. A database that prospectively tracks all LTx recipients at this academic transplant program from 1985 to 2012 was queried to identify all adult primary LTx recipients. Our post-LTx protocol incorporates GFR measurement by iothalamate clearance at regular intervals. A multistate model was used to assess the prevalence of CKD, kidney transplant, and death after LTx. Time-dependent Cox regression analysis was performed to evaluate the impact of mGFR and eGFR changes on survival. A total of 1211 transplant recipients were included. At the time of LTx, the median age was 54 years, 60% were male and 86% were Caucasian. At 25 years after LTx, 54% of patients died, 9% underwent kidney transplantation, whereas 7%, 21%, and 18% had mGFR >60, 59-30, and <30 ml/min/1.73 m(2) respectively. The risk of death increased when mGFR decreased below 30 ml/min/1.73 m(2): HR = 2.67 (95% CI = 1.80-3.96) for GFR = 29-15 ml/min/1.73 m(2) and HR = 5.47 (95% CI = 3.10-9.65) for GFR <15 ml/min/1.73 m(2). Compared to mGFR, eGFR underestimated mortality risk in LTx recipients with an eGFR of 30-90 ml/min/1.73 m(2). An overwhelming majority of LTx recipients develop CKD. The risk of death increases exponentially when GFR <30 ml/min/1.73 m(2). Creatinine-based eGFR underestimates the mortality risk in a large proportion of patients.

Outcome after liver transplantation compared with chemotherapy in colorectal cancer patients with nonresectable liver-only disease.

531 Background: Surgical treatment of colorectal liver metastases (CLM) is the only treatment option with curative potential; however, only about 10-20% of the patients are candidates for surgical resection. The majority of CLM patients has non-resectable disease, and receives palliative chemotherapy. These patients have poor prognosis with median OS of about 20-24 months after starting first-line chemotherapy and only about 10% survive five years. Methods: Individual data from patients with non-resectable liver only disease who had received liver transplantation (Ltx) (SECA-study, Hagness et al., Ann Surg. 2013) were compared to a similar group of patients with non-resectable liver only metastases included in the NORDIC VII study (first-line Flox chemotherapy ± Cetuximab, Tveit et al., J Clin Oncol. 2012). Twenty one patient included in the Ltx study were compared to 47 patients with liver only metastases included in the NORDIC VII study. All patients in the NORDIC VII study started first-line chemotherapy, whereas 57% of patients in the Ltx study had received second- or third-line chemotherapy at time of Ltx. Results: Median age of the Ltx group was 56 years (range 45-65 years) and 57 years (range 34-65 years) in the Nordic VII study. Median tumor size was 4.5cm (range 2.8-13.0cm) and 5.0cm (range 1.4-16.0cm) in the Ltx and Nordic VII groups, respectively. 5 year OS in the Ltx group was 60% compared to a 5 year OS of 9% in the NORDIC VII group. The 5 year OS of the 21 patients in the NORDIC VII data set with the longest OS was 19%. The patients in the Ltx study who had received only first-line chemotherapy at time of Ltx had a 5 year OS of 80%. Patients in the NORDIC VII study had an OS from end of second-line chemotherapy of 6-7 months. In comparison, patients with progressive disease on second-line/third-line chemotherapy at time of Ltx, had a median OS of 39 months and a 5 year OS of 30%. Conclusions: Patients with non-resectable CLMonly, has a dramatic improved OS after Ltx compared to chemotherapy. The difference could not be explained by patient selection. Selected patients with CRC obtain OS similar to Ltx patients transplanted for primary liver malignancies. Selected CRC patients should therefore be considered for Ltx. Clinical trial information: NCT01311453.

Long-term outcome analysis of liver transplantation for severe hepatic trauma

Liver transplantation (LTX) for severe hepatic trauma and its sequelae is a rare but potentially lifesaving option at the far end of the operative spectrum. This study analyzes 12 cases with LTX for hepatic trauma and its consequences from two transplant centers. A total of 2,701 consecutive liver transplants unrelated to trauma served as a control group. χ and Mann-Whitney U-tests, Kaplan-Meier analysis with log-rank tests, and Cox regression analysis were applied. Addressed were issues before, during, and after LTX. Major study end points were patient and graft survival. The posttrauma transplant recipients are significantly younger (p = 0.014), with a significantly shorter graft survival (p = 0.038), resulting in a significantly higher retransplantation rate (p = 0.043). Of the 12 patients, 11 underwent surgical treatment for hepatic trauma before LTX with 7 of 12 patients experiencing liver necrosis at the time of LTX. Short-term survival and long-term survival are not significantly different between trauma and nontrauma patients. Severity of liver trauma (Moore Score) and concomitant injuries (Injury Severity Score [ISS]) have no significant impact on patient and graft survival. Four patients with hepatic trauma were treated with two-stage LTX with anhepatic phases between 14 hours and 28 hours. Two of those patients reached long-term survival (20-22 years). LTX for severe liver trauma and its consequences seems justified in extreme cases. The high frequency of liver necrosis at the time of LTX may indicate possible shortcomings in liver packing technique or liver resection for hemorrhage control. Thus, severe hepatic trauma requires treatment by experienced liver surgeons and emergency physicians. Therapeutic study, level IV.

Epidemiology and Outcomes of Deep Surgical Site Infections Following Lung Transplantation

We conducted a retrospective study of deep surgical site infections (SSIs) among consecutive patients who underwent lung transplantation (LTx) at a single center from 2006 through 2010. Thirty-one patients (5%) developed SSIs at median 25 days after LTx. Empyema was most common (42%), followed by surgical wound infections (29%), mediastinitis (16%), sternal osteomyelitis (6%), and pericarditis (6%). Pathogens included Gram-positive bacteria (41%), Gram-negative bacteria (41%), fungi (10%) and Mycobacterium abscessus, Mycoplasma hominis and Lactobacillus sp. (one each). Twenty-three percent of SSIs were due to pathogens colonizing recipients’ native lungs at time of LTx, suggesting surgical seeding as a source. Patient-related independent risk factors for SSIs were diabetes and prior cardiothoracic surgery; procedure-related independent risk factors were LTx from a female donor, prolonged ischemic time and number of perioperative red blood cell transfusions. Mediastinitis and sternal infections were not observed among patients undergoing minimally invasive LTx. SSIs were associated with 35% mortality at 1 year post-LTx. Lengths of stay and mortality in-hospital and at 6 months and 1 year were significantly greater for patients with SSIs other than empyema. In conclusion, deep SSIs were uncommon, but important complications in LTx recipients because of their diverse microbiology and association with increased mortality.

Functional Association between a Genetic Variant in the IL-17 Receptor Gene and Chronic Rejection after Lung Transplantation

PurposeChronic rejection is the major cause of morbidity and mortality after lung transplantation (LTx). IL-17 producing cells, inducers of airway neutrophilia, have a prominent role in chronic rejection. We investigated the relationship between genetic variants in the IL-17 receptor (IL-17R) gene and the outcome (chronic rejection and death) after LTx; furthermore the functionality (airway neutrophilia) and the impact of azithromycin treatment in patients with this SNP were examined.Methods and MaterialsRecipient DNA from blood or explant lung tissue was evaluated for the IL-17R (rs879574) polymorphism by iPLEX technology on a MassARRAY and paralleled with clinical patient data.ResultsIL-17R SNP (rs879574) was successfully determined in 497 out of 568 LTx recipients, of which 124 had the A-allele (AA+AT, 24.9%) and 373 had the TT-genotype (75.1%). Independent of age, gender, LTx type, underlying disease, time of LTx and the use of azithromycin, carriers of the AA+AT variant had an increased risk for chronic rejection (CR, hazard rate: 1.47 CI: [1.069-2.028]; p=0.003), but not for mortality (hazard rate: 1.00 CI: [0.708-1.411]; p=0.14). [figure 1] The prevalence of acute rejection was significantly higher in the risk genotype (p=0.001). The genotype at risk was functionally associated with a higher % BAL neutrophilia at day 90, 180 and 360 post-LTx (p=0.023). Interestingly, azithromycin therapy was significantly more added as treatment in patients at risk (p=0.047).ConclusionsThe presence of the A-allele of an IL-17R SNP was associated with acute and chronic rejection and a functional association with airway neutrophilia.Therefore, pretransplant determination of this SNP may improve treatment and standard care. Chronic rejection is the major cause of morbidity and mortality after lung transplantation (LTx). IL-17 producing cells, inducers of airway neutrophilia, have a prominent role in chronic rejection. We investigated the relationship between genetic variants in the IL-17 receptor (IL-17R) gene and the outcome (chronic rejection and death) after LTx; furthermore the functionality (airway neutrophilia) and the impact of azithromycin treatment in patients with this SNP were examined. Recipient DNA from blood or explant lung tissue was evaluated for the IL-17R (rs879574) polymorphism by iPLEX technology on a MassARRAY and paralleled with clinical patient data. IL-17R SNP (rs879574) was successfully determined in 497 out of 568 LTx recipients, of which 124 had the A-allele (AA+AT, 24.9%) and 373 had the TT-genotype (75.1%). Independent of age, gender, LTx type, underlying disease, time of LTx and the use of azithromycin, carriers of the AA+AT variant had an increased risk for chronic rejection (CR, hazard rate: 1.47 CI: [1.069-2.028]; p=0.003), but not for mortality (hazard rate: 1.00 CI: [0.708-1.411]; p=0.14). [figure 1] The prevalence of acute rejection was significantly higher in the risk genotype (p=0.001). The genotype at risk was functionally associated with a higher % BAL neutrophilia at day 90, 180 and 360 post-LTx (p=0.023). Interestingly, azithromycin therapy was significantly more added as treatment in patients at risk (p=0.047). The presence of the A-allele of an IL-17R SNP was associated with acute and chronic rejection and a functional association with airway neutrophilia.Therefore, pretransplant determination of this SNP may improve treatment and standard care.

Lung Transplantation Outcomes in “Older” Patients: Risk vs. Benefit?

Purpose Age 65years and older is generally considered a relative contraindication to lung transplantation. We sought to define the short and medium term outcome of LTx in patients aged 65 years older vs. less than 65 years old. Methods and Materials We retrospectively reviewed our database and identified 105 patients who underwent LTx between 04/2007 and 11/2011. Follow up analysis was censored on 11/2012. Time of LTx,33 patients were 65 years or older, and 72 patients younger than 65 years. The demographic, postoperative characteristics and survival of the 2 groups were compared. Results During this period, 94 (89.5%) double and 11 (10.5%) single LTx were performed; 43 female & 62 male recipients. Majority indication, 39% COPD, 36% PF, 12% CF. Of the 11 single LTx, 6 (54.5%) and 5 (45.4%) were implanted in ≥65 yo and figure 1 ] Conclusions LTx can be performed in patients older than 65 years with acceptable short- and medium-term survival. This cohort is well selected, with limited comorbid conditions, likely biasing overall outcome. Uniquely, our center favors bilateral lung transplantation in the majority of our recipients, regardless of age. Similarities of the early- and medium-term survival and freedom from BOS between groups might be due to type II error (small sample size), donor and recipient selection and management, or both. Additional longitudinal follow up is needed at 3-years and 5-years to better evaluate long-term clinical outcomes.

Early Administration of FTY720 Prevents Chronic Airway as Well as Vascular Destruction in Experimental Rat Lung Transplantation

BackgroundChronic rejection (CR) in terms of bronchiolitis obliterans (BO) and vascular sclerosis (VS) still represents the major obstacle for pulmonary graft survival in the medium and long term course after lung transplantation (LTX). Aside from nonspecific stimuli, early acute rejection (AR) seems to be causative especially in cases of a late diagnosis or inadequate treatment. This study investigated the effects of FTY720, a new immunosuppressant that promotes lymphocyte sequestration into lymph nodes and Peyer's patches, on the development of CR after experimental LTX. MethodsA total of 50 rats underwent allogenic (F344-to-WKY) and syngenic (WKY-to-WKY) left LTX. Group 1 animals had no treatment. Group 2 animals were administered FTY720 (3 mg/kg body weight per day) at the maximum time of AR (day 14) and continued up to day 100 after LTX. Group 3 animals were treated with the same dosage of FTY720 from day 0 to 100. The grades of AR and CR were classified according to the criteria of the International Society for Heart and Lung Transplantation. ResultsWithin 14 days after allogenic LTX, all nontreated rats developed early AR followed by severe CR with VS and BO. Similar data were observed for FTY720 treatment of existing AR (group 2). Only early administration of FTY720 (at the time of LTX) significantly reduced the proportion of animals with severe acute vascular rejection (P < .001). However, all of these allografts showed high-grade acute airway inflammation. After long-term application, the chronic inflammatory response was absent; none of the allografts developed BO and VS. ConclusionOnly application of FTY720 immediately after LTX prevented lymphocyte recirculation and lung injury.

The Unique Immunophenotype of the Adaptive Immune System in Tolerant Pediatric Liver Transplant Recipients

Introduction: The adaptive immune system is known to play a central role in solid organ transplant tolerance and rejection. The aim of this study was to characterize populations of T and B cell subsets in pediatric liver transplant (LTx) recipients via immunophenotyping. We hypothesized that such analysis would identify a unique cellular immune profile of tolerance in pediatric LTx recipients. Methods: Twenty pediatric LTx recipients were classified into 3 clinical phenotypes: tolerant (TOL, n=6) with normal liver function off immunosuppression for ≥2 years; non-tolerant (NON-TOL, n=6) with a history of ≥1 rejection episode ≥1 year post-LTx on double or triple immunosuppression; stable (STA, n=8) on tacrolimus monotherapy with normal liver function and no rejection episodes ≥1 year post-LTx. PBMCs were separated from peripheral blood specimens collected at routine clinic visits. Immunophenotyping was performed with multi-color monoclonal antibody panels. Cell fluorescence was acquired on an LSR FortessaTM cell analyzer. Population measurements were determined using FCS Express V4 analysis software. Non-transplanted, healthy young-adults (n=3) were used as controls to establish and validate flow panels. Statistical analyses included fisher's exact, Kruskal-wallis, and t-tests. Results are reported as mean ± SD. Results: As shown in the Table, TOL patients tended to be younger at the time of LTx and older at the time of sample collection. All TOL patients were males. As also shown in the table, T and B cell populations varied across groups. TOL patients had a significantly greater proportion of naïve CD4+RA+ T cells and smaller populations of central memory CD4+CD197+RA- T cells compared to NON-TOL and STA. TOL patients had a trend towards lower proportions of memory B cells (CD19+CD27+) and higher proportions of transitional (CD27CD-38++IgD+) and unswitched memory (CD27+IgD+IgM+) B cells compared to NON-TOL patients. TOL patients also had increased naïve CD4+CD197+RA+ T cells, CD4+CD25+CD127l0 regulatory T cells, and inducible CD4+CD25+CD127l0RA- T cells (data not shown).Table: [Results for TOL, NON-TOL, and STA LTx recipients]Conclusion: This study represents the most comprehensive analysis of T and B cell immunophenotypes in pediatric LTx recipients to date. We have shown that TOL patients have a unique adaptive immune system cellular profile characterized by smaller populations of central memory T cells and larger populations of naïve and regulatory T cells as well as transitional and unswitched memory B cells. This may lead to fewer effector T cells and increased production of regulatory cytokines, ultimately creating an overall tolerogenic environment. We are currently immunophenotyping a larger cohort of patients to further delineate the unique features of tolerance and discriminate them from the effects of immunosuppression.

Outcomes and temporal trends among high-risk patients after lung transplantation in the United States

Although several studies have evaluated risk factors for death after lung transplantation (LTx), few studies have focused on the highest-risk recipients. We undertook this study to evaluate the effect of high lung allocation scores (LAS), ventilator support, and extracorporeal membrane oxygenation (ECMO) support on outcomes after LTx. We retrospectively reviewed all LTx recipients in the United Network for Organ Sharing database. Primary stratification was by recipient acuity at the time of LTx. The 3 strata consisted of (1) recipients in the highest LAS quartile (LAS ≥ 48.4), (2) those requiring ventilator support, and (3) those requiring ECMO support. The primary outcome was 1-year mortality. Sub-group analysis focused on temporal trends. From May 2005 to June 2011, 9,267 adults underwent LTx. Before LTx, 1,874 (20.2%) were in the highest LAS quartile, 526 (5.7%) required ventilator support, and 122 (1.3%) required ECMO support. Unadjusted analysis showed decreased 1-year survival associated with ventilator (67.7%) and ECMO support (57.6%) compared with the highest LAS quartile (81.0%; p < 0.001 for each comparison). These differences persisted on adjusted analysis for ventilator support (hazard ratio, 1.99, p < 0.001) and ECMO support (hazard ratio, 3.03; p < 0.001). Increasing annual center volume was associated with decreased mortality. In patients bridged to LTx with ECMO support, 1-year survival improved over time (coefficient, 8.03% per year; p = 0.06). High-acuity LTx recipients, particularly those bridged with ventilator or ECMO support, have increased short-term mortality after LTx. However, since the introduction of the LAS, high-risk patients have demonstrated improving outcomes, particularly at high-volume centers.

Colorectal neoplasia in patients with primary sclerosing cholangitis undergoing liver transplantation: a Nordic multicenter study

Objective. Several studies have implicated primary sclerosing cholangitis (PSC) as an additional risk factor for colorectal neoplasia in inflammatory bowel disease (IBD). Some reports have indicated that the risk is even higher in PSC-IBD patients after liver transplantation (Ltx), but this issue is controversial. We aimed to compare the risk of colorectal neoplasia in PSC-IBD patients before and after Ltx and to identify risk factors for colorectal neoplasia post-transplant. Material and methods. In a multicenter study within the Nordic Liver Transplant Group, we assessed the risk of colorectal neoplasia by using the competing risk regression analysis. Results. Among the 439 PSC patients included, 353 (80%) had IBD at the time of Ltx and 15 (3%) patients developed de novo IBD post-Ltx. The median duration of IBD was 15 (0–50) years at the time of Ltx and follow-up after Ltx was 5 (0–20) years. Ninety-one (25%) PSC-IBD patients developed colorectal neoplasia. The cumulative risk of colorectal neoplasia was higher after than before Ltx (HR: 1.9, 95% CI: 1.3–2.9, p = 0.002). A multivariate analysis demonstrated aminosalicylates and ursodeoxycholic acid as significantly associated with an increased risk of colorectal neoplasia post-Ltx. Duration and activity of IBD did not significantly affect the risk of neoplasia. Conclusion. The even higher risk of colorectal neoplasia in PSC-IBD patients after when compared with that of before Ltx underscores the importance of regular surveillance colonoscopies post-Ltx. The association of aminosalicylates and ursodeoxycholic acid to the development of colorectal neoplasia after Ltx should be further investigated.

Preoperative Recipient Cytokine Levels Are Associated With Early Lung Allograft Dysfunction

Primary graft dysfunction (PGD) is a morbid complication after lung transplant (LTx). Recipient before and after cytokine and chemokine profiles may be associated with a recipient's propensity to have PGD. Serum samples were obtained from adult (more than 17 years old) primary LTx recipients (2002 to 2007) at two time points: (1) pre-reperfusion of transplanted lungs, and (2) within 24 hours after reperfusion. Interleukin (IL)-6, IL-8, IL-10, chemokine ligand (CCL)-2, and matrix metalloproteinase (MMP)-9 levels were determined. A PaO2/FiO2 ratio less than 300 at 48 hours (International Society for Heart and Lung Transplantation PGD grade 2 or more) was used to stratify patients. Follow-up was obtained through August 2009. Cytokine levels at both time points and the change in levels were assessed for association with PGD grade 2 or more. Outcomes and clinical characteristics were analyzed. Of 28 patients, 8 (28.6%) had PGD grade 2 or more. Median follow-up was 23 months (interquartile range, 16 to 31). Demographics, clinical data, and pre-LTx diagnoses did not differ between the groups. Patients who had PGD grade 2 or more had higher baseline levels of IL-10, IL-8, IL-6, and CCL-2 (all p<0.05). Within 24 hours, PGD grade 2 or more patients had higher IL-10 (p=0.02) and CCL-2 (p=0.04) levels. The PGD grade 2 or more patients were more likely to have had cardiopulmonary bypass during LTx (p=0.002) and blood products administered: platelets (p=0.004), plasma (p=0.05), and packed red blood cells (p=0.03)]. The PGD grade 2 or more patients had longer length of stay, duration of mechanical ventilation, and total intensive care unit days. Higher before and after transplant cytokine/chemokine levels were found in LTx recipients who subsequently had PGD grade 2 or more. Our study demonstrates that the recipient's inflammatory state at the time of LTx may impact early allograft function. That could represent a potential target for pretransplant pharmacologic intervention.

Duct-to-duct biliary reconstruction in patients with primary sclerosing cholangitis undergoing liver transplantation

BackgroundReconstruction of biliary drainage after liver transplantation (LTx) in patients with primary sclerosing cholangitis (PSC) has been a matter of controversy. Over recent years, the traditional method of Roux-en-Y hepaticojejunostomy (RY) has been challenged by duct-to-duct (DD) biliary reconstruction. MethodsThis study represents a retrospective review of biliary complications, patient and graft survival after LTx in PSC patients based on type of biliary reconstruction. Outcomes of DD reconstruction in this group of patients and non-PSC patients are compared. ResultsA total of 53 primary LTx procedures were performed for PSC between August 2005 and July 2010. Seven patients were excluded because unexpected cholangiocarcinoma was found in the explants (n= 3) or because they received partial livers (n= 4). Biliary reconstruction was performed as DD in 18 patients and RY in 28 patients. There were no bile leaks. Anastomotic stricture occurred in two (11%) patients in the DD group and one (4%) in the RY group. Two (7%) patients in the RY group developed non-PSC intrahepatic strictures and one had recurrence of PSC. Rates of 1- and 3-year patient and graft survival in the RY and DD groups were 96.7% and 96.7%, and 100% and 94.5%, respectively. In a group of 34 randomly selected patients transplanted for a non-PSC diagnosis with DD reconstruction during the same period, the anastomotic stricture rate was 9% and 1- and 3-year patient and graft survival rates were 97.0% and 88.5%; differences were not significant. ConclusionsDuct-to-duct biliary reconstruction at the time of LTx in selected PSC patients is both effective and safe, and shows outcomes comparable with those of RY reconstruction in these patients and those of DD reconstruction in non-PSC patients.

Lung transplantation after hematopoietic stem cell transplantation

Pulmonary insufficiency following bone marrow transplant (BMT) is common and has significant associated mortality. Lung transplantation (LTX) is the only viable treatment for patients with end-stage pulmonary disease, but LTX after BMT is an uncommon event given the medical candidacy of the potential recipients. We sought to evaluate the short- and long-term outcomes of LTX in BMT recipients. We performed a retrospective evaluation of our institution's longitudinal LTX and BMT databases. Demographic and outcomes variables were collected. We identified 639 LTX from January 1, 1988, through December 31, 2009, and 5525 BMT from program inception, March 21, 1974, through December 31, 2009. From the cross-referenced cohort, we identified four patients who had BMT followed by LTX. Our series was composed of two men and two women, with a mean age of 32.3 yr (range, 20-59 yr). Single LTX were performed in two recipients (50%). All patients had significant and expected morbidities related to their transplant immunosuppression. Three patients (75%) required cardiopulmonary bypass at the time of LTX. The two recipients who underwent bilateral LTX required open chest management and subsequent tracheostomy. All patients are still alive at follow-up (range, 19-119 months, median 39.5). Our study demonstrates that LTX in the setting of BMT is a high-risk operation with the potential for a tumultuous perioperative course. Despite this, good outcomes and survival are obtainable in carefully selected patients. Selection factors include clinically stable patients without active sepsis and preoperative optimization of nutrition in anticipation of a prolonged recovery. An experienced multidisciplinary team approach and a protocol-driven management plan are paramount for successful outcomes in this challenging population.