Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer.

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

Cas phosphorylation regulates focal adhesion assembly.

Integrin-mediated cell attachment rapidly induces tyrosine kinase signaling. Despite years of research, the role of this signaling in integrin activation and focal adhesion assembly is unclear. We provide evidence that the Src-family kinase (SFK) substrate Cas (Crk-associated substrate, p130Cas, BCAR1) is phosphorylated and associated with its Crk/CrkL effectors in clusters that are precursors of focal adhesions. The initial phospho-Cas clusters contain integrin ß1 in its inactive, bent closed, conformation. Later, phospho-Cas and total Cas levels decrease as integrin ß1 is activated and core focal adhesion proteins including vinculin, talin, kindlin, and paxillin are recruited. Cas is required for cell spreading and focal adhesion assembly in epithelial and fibroblast cells on collagen and fibronectin. Cas cluster formation requires Cas, Crk/CrkL, SFKs, and Rac1 but not vinculin. Rac1 provides positive feedback onto Cas through reactive oxygen, opposed by negative feedback from the ubiquitin proteasome system. The results suggest a two-step model for focal adhesion assembly in which clusters of phospho-Cas, effectors and inactive integrin ß1 grow through positive feedback prior to integrin activation and recruitment of core focal adhesion proteins.

A Cas-BCAR3 co-regulatory circuit controls lamellipodia dynamics.

Integrin adhesion complexes regulate cytoskeletal dynamics during cell migration. Adhesion activates phosphorylation of integrin-associated signaling proteins, including Cas (p130Cas, BCAR1), by Src-family kinases. Cas regulates leading-edge protrusion and migration in cooperation with its binding partner, BCAR3. However, it has been unclear how Cas and BCAR3 cooperate. Here, using normal epithelial cells, we find that BCAR3 localization to integrin adhesions requires Cas. In return, Cas phosphorylation, as well as lamellipodia dynamics and cell migration, requires BCAR3. These functions require the BCAR3 SH2 domain and a specific phosphorylation site, Tyr 117, that is also required for BCAR3 downregulation by the ubiquitin-proteasome system. These findings place BCAR3 in a co-regulatory positive-feedback circuit with Cas, with BCAR3 requiring Cas for localization and Cas requiring BCAR3 for activation and downstream signaling. The use of a single phosphorylation site in BCAR3 for activation and degradation ensures reliable negative feedback by the ubiquitin-proteasome system.

Prediction of VRC01 neutralization sensitivity by HIV-1 gp160 sequence features.

The broadly neutralizing antibody (bnAb) VRC01 is being evaluated for its efficacy to prevent HIV-1 infection in the Antibody Mediated Prevention (AMP) trials. A secondary objective of AMP utilizes sieve analysis to investigate how VRC01 prevention efficacy (PE) varies with HIV-1 envelope (Env) amino acid (AA) sequence features. An exhaustive analysis that tests how PE depends on every AA feature with sufficient variation would have low statistical power. To design an adequately powered primary sieve analysis for AMP, we modeled VRC01 neutralization as a function of Env AA sequence features of 611 HIV-1 gp160 pseudoviruses from the CATNAP database, with objectives: (1) to develop models that best predict the neutralization readouts; and (2) to rank AA features by their predictive importance with classification and regression methods. The dataset was split in half, and machine learning algorithms were applied to each half, each analyzed separately using cross-validation and hold-out validation. We selected Super Learner, a nonparametric ensemble-based cross-validated learning method, for advancement to the primary sieve analysis. This method predicted the dichotomous resistance outcome of whether the IC50 neutralization titer of VRC01 for a given Env pseudovirus is right-censored (indicating resistance) with an average validated AUC of 0.868 across the two hold-out datasets. Quantitative log IC50 was predicted with an average validated R2 of 0.355. Features predicting neutralization sensitivity or resistance included 26 surface-accessible residues in the VRC01 and CD4 binding footprints, the length of gp120, the length of Env, the number of cysteines in gp120, the number of cysteines in Env, and 4 potential N-linked glycosylation sites; the top features will be advanced to the primary sieve analysis. This modeling framework may also inform the study of VRC01 in the treatment of HIV-infected persons.

Early clinical complications after ABO-incompatible live-donor kidney transplantation: a national study of Medicare-insured recipients.

BACKGROUND: Descriptions of the sequelae of ABO-incompatible (ABOi) kidney transplantation are limited to single-center reports, which may lack power to detect important effects. METHODS: We examined U.S. Renal Data System registry data to study associations of ABOi live-donor kidney transplantation with clinical complications in a national cohort. Among 14,041 Medicare-insured transplants in 2000 to 2007, 119 non-donor-A2 ABOi transplants were identified. A2-incompatible (n=35) transplants were categorized separately. Infection and hemorrhage events were identified by diagnosis codes on billing claims. Associations of ABO incompatibility with complications were assessed by multivariate Cox regression. RESULTS: Recipients of ABOi transplants experienced significantly (P<0.05) higher incidence of wound infections (12.7% vs. 7.3%), pneumonia (7.6% vs. 3.8%), and urinary tract infections (UTIs) or pyelonephritis (24.5% vs. 15.3%) in the first 90 days compared with ABO-compatible recipients. In adjusted models, ABO incompatibility was associated with twice the risk of pneumonia (adjusted hazard ratio [aHR], 2.22; 95% confidence interval [CI], 1.14-4.33) and 56% higher risk of UTIs or pyelonephritis (aHR, 1.56; 95% CI, 1.05-2.30) in the first 90 posttransplantation days, and 3.5 times the relative risk of wound infections in days 91 to 365 (aHR, 3.55; 95% CI, 1.92-6.57). ABOi recipients, 19% of whom underwent pre- or peritransplant splenectomy, experienced twice the adjusted risk of early hemorrhage (aHR, 1.96; 95% CI, 1.19-3.24). A2-incompatible transplantation was associated only with early risk of UTIs or pyelonephritis. CONCLUSION: ABOi transplantation offers patients with potential live donors an additional transplant option but with higher risks of infectious and hemorrhagic complications. Awareness of these complications may help improve protocols for the management of ABOi transplantation.

Outcomes of renal transplants from Centers for Disease Control and Prevention high-risk donors with prospective recipient viral testing: a single-center experience.

HYPOTHESIS: The use of kidneys from deceased donors considered at increased infectious risk represents a strategy to increase the donor pool. DESIGN: Single-institution longitudinal observational study. SETTING: Tertiary care center. PATIENTS: Fifty patients who gave special informed consent to receive Centers for Disease Control and Prevention high-risk (CDCHR) donor kidneys were followed up by serial testing for viral transmission after transplantation. Nucleic acid testing for human immunodeficiency virus, hepatitis B virus, and hepatitis C virus was performed on all high-risk donors before transplantation. Outcomes of CDCHR kidney recipients were compared with outcomes of non-high-risk (non-HR) kidney recipients. MAIN OUTCOME MEASURES: New viral transmission, graft function, and waiting list time. RESULTS: No recipient seroconversion was detected during a median follow-up period of 11.3 months. Compared with non-HR donors, CDCHR donors were younger (mean [SD] age, 35 [11] vs 43 [18] years, P = .01), fewer were expanded criteria donors (2.0% vs 24.8%, P < .001), and fewer had a terminal creatinine level exceeding 2.5 mg/dL (4.0% vs 8.8%, P = .002). The median creatinine levels at 1 year after transplantation were 1.4 (interquartile range, 1.2-1.7) mg/dL for CDCHR recipients and 1.4 (interquartile range, 1.1-1.9) mg/dL for non-HR recipients (P = .4). Willingness to accept a CDCHR kidney significantly shortened the median waiting list time (274 vs 736 days, P < .001). CONCLUSIONS: We show safe use of CDCHR donor kidneys and good 1-year graft function. With continued use of these organs and careful follow-up care, we will be better able to gauge donor risk and match it to recipient need to expand the donor pool and optimize patient benefit.

Desensitization in HLA-incompatible kidney recipients and survival.

BACKGROUND: More than 20,000 candidates for kidney transplantation in the United States are sensitized to HLA and may have a prolonged wait for a transplant, with a reduced transplantation rate and an increased rate of death. One solution is to perform live-donor renal transplantation after the depletion of donor-specific anti-HLA antibodies. Whether such antibody depletion results in a survival benefit as compared with waiting for an HLA-compatible kidney is unknown. METHODS: We used a protocol that included plasmapheresis and the administration of low-dose intravenous immune globulin to desensitize 211 HLA-sensitized patients who subsequently underwent renal transplantation (treatment group). We compared rates of death between the group undergoing desensitization treatment and two carefully matched control groups of patients on a waiting list for kidney transplantation who continued to undergo dialysis (dialysis-only group) or who underwent either dialysis or HLA-compatible transplantation (dialysis-or-transplantation group). RESULTS: In the treatment group, Kaplan-Meier estimates of patient survival were 90.6% at 1 year, 85.7% at 3 years, 80.6% at 5 years, and 80.6% at 8 years, as compared with rates of 91.1%, 67.2%, 51.5%, and 30.5%, respectively, for patients in the dialysis-only group and rates of 93.1%, 77.0%, 65.6%, and 49.1%, respectively, for patients in the dialysis-or-transplantation group (P<0.001 for both comparisons). CONCLUSIONS: Live-donor transplantation after desensitization provided a significant survival benefit for patients with HLA sensitization, as compared with waiting for a compatible organ. By 8 years, this survival advantage more than doubled. These data provide evidence that desensitization protocols may help overcome incompatibility barriers in live-donor renal transplantation. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Charles T. Bauer Foundation.).

Outcomes and discard of kidneys from pediatric donors after cardiac death.

BACKGROUND: Kidney transplants from pediatric donors after cardiac death (PDCD) have quadrupled in the past 9 years, but little data exist on outcomes using these donors. We hypothesized that pediatric organs might be more sensitive to the pathophysiology of cardiac death. METHODS: We evaluated outcomes and rates of discard of more than 12,000 pediatric kidneys recovered between 2000 and 2009. We compared short- and long-term graft function among adult and pediatric recipients of PDCD kidneys compared with recipients of pediatric kidneys from donors after brain death (PDBD). RESULTS: Overall, 6.3% of pediatric kidneys recovered were PDCD and 93.7% were PDBD. Discard rates were higher for PDCD kidneys (adjusted odds ratio=1.69, 95% confidence interval [CI]=1.31-2.18, P<0.001). Delayed graft function (DGF) was twice as common in recipients of PDCD grafts compared with PDBD (26.2% vs. 13.0%, P<0.001); however, among pediatric recipients, DGF rates were half of those observed in adults, and a statistically significant difference in DGF could not be detected between PDBD and PDCD grafts (6.9% vs. 4.9%, P=0.6). Among all recipients, PDCD kidneys had a greater risk of graft loss compared with PDBD kidneys (adjusted hazard ratio=1.32, 95% CI=1.06-1.65, P=0.01), although among pediatric recipients this increased risk was not statistically significant (adjusted hazard ratio=2.01, 95% CI=0.89-4.54, P=0.1). CONCLUSIONS: The differences in outcomes between adult recipients of PDCD and PDBD kidneys, and the attenuation of these differences among pediatric recipients, should be weighed against risks of prolonged waitlist time in recipients being considered for these grafts.

ABO incompatible renal transplantation: a paradigm ready for broad implementation.

The requirements for potent immunosuppression coupled with the formidable risk of irreversible antibody-mediated rejection (AMR) have thus far limited the expansion of ABO incompatible (ABOi) kidney transplantation. We present a retrospective review of our single-center experience with 60 consecutive ABOi kidney transplants and describe the evolution of our treatment protocol to one that consists only of a brief escalation in immunosuppression without long-term B-cell suppression from splenectomy or anti-CD20. The 1-, 3-, and 5-year graft survival rates for the cohort were 98.3%, 92.9%, and 88.7%, respectively, which is comparable with United Network for Organ Sharing data for compatible live donor transplants. No instances of hyperacute rejection were observed, and no grafts were lost secondary to AMR. In fact, fewer than 15% of the patients experienced a clinical episode of AMR, and rejections were mild. Elimination of B-cell ablative therapies did not result in an increased incidence of AMR. Excellent graft function persists with a current median creatinine clearance of 60 mL/min. The findings of this study and the relatively simple therapeutic regimen used should facilitate widespread application of ABOi kidney transplantation resulting in one of the most rapid escalations in access to organs in the modern era of kidney transplantation.

Rapid accomodation of an A1 renal allograft after preconditioning for ABO-incompatible transplantation.

BACKGROUND: Successful ABO-incompatible (ABOi) kidney transplantation of non-A2 renal allografts requires preconditioning to reduce anti-blood group antibody to safe lev-els in order to avoid hyperacute rejection. Unfortunately, early post-transplant acute antibody-mediated rejection remains a problem in these patients and can result in rapid graft loss. A number of investigators have encountered ABOi recipients who have had no evidence of allograft injury in the setting of elevated titers of anti-ABO antibody, a protective phenomenon that has been termed 'accommodation'. Little is known about the time course of accommodation. We report a case of a successful ABOi renal transplant recipient who had evidence of accommodation within the first week following transplantation. CASE REPORT: The patient is a 36-year-old, highly sensitized blood group.woman who underwent live donor transplantation from her human leukocyte antigen-identical blood group A1 brother following therapy with plasmapheresis and low-dose intravenous immunoglobulin for an initial anti-A anti-human globulin antibody titer of 512. Within the first week following transplantation, her anti-A titer rose to 128 without change in her renal function. At 1 month following transplantation, her anti-A titer had risen to 256 at which time a biopsy was per-formed that demonstrated no evidence of antibody-mediated rejection. CONCLUSION: This patient demonstrates that accommodation of the renal allograft following ABOi transplantation may take place in the early postoperative period in the setting of high titer antibody. The implications for postoperative management of the ABOi patient and the need for future investigation in this area are discussed.

C4d deposition without rejection correlates with reduced early scarring in ABO-incompatible renal allografts.

C4d deposition in peritubular capillaries is a specific marker for the presence of antidonor antibodies in renal transplant recipients and is usually associated with antibody-mediated rejection (AMR) in conventional allografts. In ABO-incompatible grafts, however, peritubular capillary C4d is often present on protocol biopsies lacking histologic features of AMR; the significance of C4d in this setting remains unclear. For addressing this, data from 33 patients who received ABO-incompatible renal allografts (after desensitization) were retrospectively reviewed. Protocol biopsies were performed at 1 and/or 3 and 6 mo after transplantation in each recipient and at 12 mo in 28 recipients. Twenty-one patients (group A) had strong, diffuse peritubular capillary C4d staining without histologic evidence of AMR or cellular rejection on their initial protocol biopsies. The remaining 12 patients (group B) had negative or weak, focal peritubular capillary C4d staining. Three grafts (two in group B) were lost but not as a result of AMR. Excluding these three patients, serum creatinine levels were similar in the two groups at 6 and 12 mo after transplantation and at last follow-up; however, recipients in group A developed significantly fewer overall chronic changes, as scored by the sum of Banff chronic indices, than group B during the first year after transplantation. These results suggest that diffuse peritubular capillary C4d deposition without rejection is associated with a lower risk for scarring in ABO-incompatible renal allografts; the generalizability of these results to conventional allografts remains unknown.

The fate of anti-HLA antibody among renal transplantation recipients treated with bortezomib.

We present four cases of renal transplant recipients who were treated with bortezomib for four different indications, each of whom had circulating anti-HLA antibodies that were followed serially throughout their courses of bortezomib therapy. It is important to note that each patient was administered bortezomib in conjunction with other agents and therapies traditionally used for desensitization or the treatment of AMR. The results have been mixed. In some cases substantial decreases in HLA-antibody were temporally related to bortezomib therapy. In the one case of recalcitrant AMR there has been no reduction in DSA after 2 cycles of the drug. Bortezomib has been well tolerated. One patient developed reversible peripheral neuropathic pain while another experienced line sepsis, a urinary tract infection, and an invasive fungal skin infection. Again, this patient had also received protracted courses of plasmapheresis combined with T-cell and B-cell depleting agents. The use of these other drugs precludes the ability to rigorously evaluate the efficacy of bortezomib in isolation and points towards a need for large-scale, controlled trials to determine whether the drug's promising mechanism of action is applicable in the setting of solid organ transplantation.

Prolonged waiting times for liver transplantation in obese patients.

OBJECTIVE: To quantify the independent association between obesity and access to liver transplantation. BACKGROUND: Obesity is associated with higher complication rates, longer hospitalization, and worse survival after liver transplantation. Nevertheless, transplantation provides survival benefit to patients with end-stage liver disease, regardless of body mass index (BMI). We hypothesized that, despite survival benefit, providers were reluctant to transplant obese patients because of the inherent difficulty of these cases and their inferior outcomes. Our goal was to quantify the independent association between BMI and waiting time for orthotopic liver transplantation as a surrogate marker for this reluctance. METHODS: We studied 29,136 wait-list candidates in the model for end-stage liver disease (MELD) era, categorized as severely obese (BMI 35-40), morbidly obese (BMI 40-60), and reference (BMI 18.5-35). All models were adjusted for factors relevant to the allocation system, factors possibly influencing access to healthcare, and factors biologically related to disease progression and outcomes. RESULTS: The odds of receiving a MELD exception were 30% lower in severely obese and 38% lower in morbidly obese patients. Similarly, the likelihoods of being turned down for an organ were 10% and 16% higher, and the rates of being transplanted were 11% and 29% lower in severely obese and morbidly obese patients, respectively. CONCLUSIONS: Current practice seems to indicate a reluctance to transplant obese patients. If indeed as a community we feel that liver allografts should not be distributed to patients with excessive postoperative risk, we should consider expressing this as a formal change to our allocation policy rather than through informal practice patterns.

Donor ethnicity influences outcomes following deceased-donor kidney transplantation in black recipients.

Although the majority of deceased-donor kidneys are donated after brain death, increased recovery of kidneys donated after cardiac death could reduce the organ shortage and is now a national priority. Racial disparities in donations after brain death have been well described for renal transplantation, but it is unknown whether similar disparities occur in donations after cardiac death. In this study, outcomes of adult deceased-donor renal transplant recipients included in the United Network for Organ Sharing database (1993 through 2006) were analyzed. Among black recipients of kidneys obtained after cardiac death, those who received kidneys from black donors had better long-term graft and patient survival than those who received kidneys from white donors. In addition, compared with standard-criteria kidneys from white donors after brain death, kidneys from black donors after cardiac death conferred a 70% reduction in the risk for graft loss (adjusted hazard ratio 0.30; 95% confidence interval 0.14 to 0.65; P = 0.002) and a 59% reduction in risk for death (adjusted hazard ratio 0.41; 95% confidence interval 0.2 to 0.87; P = 0.02) among black recipients. These findings suggest that kidneys obtained from black donors after cardiac death may afford the best long-term survival for black recipients.

Pretransplant panel reactive antibodies in human lung transplantation: an analysis of over 10,000 patients.

BACKGROUND: The role of panel reactive antibody (PRA) in lung transplant recipients has not been clearly defined in a large population. We sought to determine how panel reactive antibody level affects survival in lung transplant recipients. METHODS: The United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research files from 1987 through 2005 were analyzed. Demographic data, pretransplant PRA, relevant clinical indicators, and survival were examined. RESULTS: Of the 12,751 first lung transplant recipients during this period, pretransplant PRA levels were reported for 10,237 patients. Panel reactive antibody was more than 0% in 1748 patients; of these, PRA was 1% to 10% in 1259 (72%), 11% to 25% in 249 (14%), and more than 25% in 240 (14%). Using the Kaplan-Meier method, survival decreased with increasing PRA and was significant when PRA exceeded 25% compared with the rest of the cohort. On multivariable analysis, PRA was associated with increased 30-day (hazard ratio, 2.6) and overall mortality (hazard ratio, 1.3). Importantly, this effect was not seen when a cohort from 1998 through 2005 was analyzed. CONCLUSIONS: The UNOS database has provided the largest series of lung transplant patients stratified by PRA. Our analysis demonstrates that PRA level exceeding 25% is a predictor of death. However, newer laboratory and management techniques may attenuate this effect with better outcomes in the modern era.

Declining outcomes in simultaneous liver-kidney transplantation in the MELD era: ineffective usage of renal allografts.

BACKGROUND: When the United Network for Organ Sharing changed its algorithm for liver allocation to the model for end-stage liver disease (MELD) system in 2002, highest priority shifted to patients with renal insufficiency as a major component of their end-stage liver disease. An unintended consequence of the new system was a rapid increase in the number of simultaneous liver-kidney transplants (SLK) being performed yearly. METHODS: Adult recipients of deceased donor liver transplants (LT, n=19,137), kidney transplants (n=33,712), and SLK transplants (n=1,032) between 1987 and 2006 were evaluated based on United Network for Organ Sharing data. Recipients were stratified by donor subgroup, MELD score, pre- versus post-MELD era, and length of time on dialysis. Matched-control analyses were performed, and graft and patient survival were analyzed by Kaplan-Meier and Cox proportional hazards analyses. RESULTS: MELD era outcomes demonstrate a decline in patient survival after SLK. Using matched-control analysis, we are unable to demonstrate a benefit in the SLK cohort compared with LT, despite the fact that higher quality allografts are being used for SLK. Subgroup analysis of the SLK cohort did demonstrate an increase in overall 1-year patient and liver graft survival only in those patients on long-term dialysis (> or =3 months) compared with LT (84.5% vs. 70.8%, P=0.008; hazards ratio 0.57 [95% CI 0.34, 0.95], P=0.03). CONCLUSION: These findings suggest that SLK may be overused in the MELD era and that current prioritization of kidney grafts to those liver failure patients results in wasting of limited resources.

Obesity impacts access to kidney transplantation.

Current billing practices and mandates to report surgical outcomes are disincentives to surgical treatment of obese patients, who are at increased risk for longer hospital stays and higher complication rates. The objective of this study was to quantify the independent association between body mass index (BMI) and waiting time for kidney transplantation to identify potential provider bias against surgical treatment of the obese. A secondary data analysis was performed of a prospective cohort of 132,353 patients who were registered for kidney transplantation in the United States between 1995 and 2006. Among all patients awaiting kidney transplantation, the likelihood of receiving a transplant decreased with increasing degree of obesity, categorized by ranges of BMI (adjusted hazard ratios 0.96 for overweight, 0.93 for obese, 0.72 for severely obese, and 0.56 for morbidly obese, compared with a reference group of patients with normal BMI). Similarly, the likelihood of being bypassed when an organ became available increased in a graded manner with category of obesity (adjusted incidence rate ratio 1.02 for overweight, 1.05 for obese, 1.11 for severely obese, and 1.22 for morbidly obese). Although matching an available organ with an appropriate recipient requires clinical judgment, which could not be fully captured in this study, the observed differences are dramatic and warrant further studies to understand this effect better and to design a system that is less susceptible to unintended bias.

Minimizing risk associated with elderly liver donors by matching to preferred recipients.

UNLABELLED: Elderly liver donors (ELDs) represent a possible expansion of the donor pool, although there is great reluctance to use ELDs because of reports that increasing donor age predicts graft loss and patient death. The goal of this study was to identify a subgroup of recipients who would be least affected by increased donor age and thus best suited to receive grafts from ELDs. A national registry of deceased donor liver transplants from 2002-2005 was analyzed. ELDs aged 70-92 (n = 1043) were compared with average liver donors (ALDs) aged 18-69 (n = 15,878) and ideal liver donors (ILDs) aged 18-39 (n = 6842). Recipient factors that modified the effect of donor age on outcomes were identified via interaction term analysis. Outcomes in recipient subgroups were compared using Kaplan-Meier survival analysis. Recipients preferred for ELD transplants were determined to be first-time recipients over the age of 45 with body mass index <35, non-status 1 registration, cold ischemic time <8 hours, and either hepatocellular carcinoma or an indication for transplantation other than hepatitis C. In preferred recipients, there were no differences in outcomes when ELD livers were used (3-year graft survival: ELD 75%, ALD 75%, ILD 77%, P > 0.1; 3-year patient survival: ELD 81%, ALD 80%, ILD 81%, P > 0.1). In contrast, there were significantly worse outcomes when ELD livers were used in nonpreferred recipients (3-year graft survival: ELD 50%, ALD 71%, ILD 75%, P < 0.001; 3-year patient survival: ELD 64%, ALD 77%, ILD 80%, P < 0.001). CONCLUSION: The risks of ELDs can be substantially minimized by appropriate recipient selection.

Twenty years of liver transplantation for Budd-Chiari syndrome: a national registry analysis.

Several treatment options exist for the management of Budd-Chiari syndrome (BCS), yet the relative role and timing of liver transplantation (LT) remain poorly defined. Small case series published to date have not been able to delineate the impact of comorbidities and thromboembolic complications of BCS on survival after LT. To better understand the outcomes after LT for BCS, we analyzed 510 liver transplants performed for this disease in the United States between 1987 and 2006. Risk factors predicting graft loss or patient death included increased recipient age, hyperbilirubinemia, elevated creatinine, life support or hospitalization at the time of transplantation, prior transplantation, prior abdominal surgery, increased donor age, and prolonged cold ischemic time (CIT). Prior transjugular intrahepatic portosystemic shunt (TIPS) was not associated with worse outcomes. Transplantation in the Model for End-Stage Liver Disease (MELD) era was associated with significantly lower risk of graft loss (hazard ratio [HR], 0.50; 95% confidence interval [CI], 0.30-0.86; P = 0.012) and death (HR, 0.52; 95% CI, 0.29-0.93; P = 0.027). Similarly, MELD era was associated with significantly lower risk of early graft loss (odds ratio [OR], 0.35; 95% CI, 0.16-0.79, P = 0.012) and early death (odds ratio, 0.37; 95% CI, 0.14-0.95; P = 0.040). However, patients with BCS transplanted in the MELD era were less likely to have life support, hospitalization, prior transplants, and prolonged cold ischemia times. In conclusion, outcomes of LT for BCS are excellent, with further improvements since 2002 associated with a selection shift imposed by MELD-based organ allocation.

Impact of bilateral versus single lung transplantation on survival in recipients 60 years of age and older: analysis of United Network for Organ Sharing database.

OBJECTIVE: Lung transplantation has been increasingly applied to patients over the age of 60 years. Importantly, the procedure of choice, single versus bilateral lung transplantation, remains unclear. Therefore, the purpose of this study was to examine short- and midterm outcomes in this age group with particular attention to procedure type. METHODS: All first lung transplant recipients, 60 years of age or older, reported to the United Network for Organ Sharing from 1998 to 2004 were divided into two groups: bilateral and single lung transplantation. A retrospective review of pertinent baseline characteristics, clinical parameters, and outcomes was performed. Kaplan-Meier methodology was used to estimate and Cox proportional hazards regression modeling was used to compare posttransplant survival between these groups. Additionally, propensity scores analysis was performed. RESULTS: During the study period, 1656 lung transplant recipients were 60 years of age or older (mean 62.7 +/- 2.4 years, median 62 years). Of these, 364 (28%) had bilateral and 1292 (78%) had single lung transplantation. Survival was not statistically different between the two groups. In the multivariate analysis, bilateral versus single lung transplantation was not a predictor of mortality. Idiopathic pulmonary fibrosis and a donor tobacco history of more than 20 pack-years were significantly associated with mortality (P = .003, CI 1.12-1.76; and P = .006, CI 1.09-1.63; respectively). CONCLUSIONS: The survival of lung transplant recipients 60 years of age or older who underwent bilateral versus single lung transplantation is comparable. These data suggest that type of procedure is not a predictor of mortality in this age group. Idiopathic pulmonary fibrosis and donor cigarette use of more than 20 pack-years were independently associated with mortality.