A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

Early technical pancreas failure in Simultaneous Pancreas-Kidney Recipients does not impact renal allograft outcomes.

Early pancreas loss in simultaneous pancreas-kidney (SPK) transplants has been associated with longer perioperative recovery and reduced kidney allograft function. We assessed the impact of early pancreas allograft failure on transplant outcomes in a contemporary cohort of SPK patients (n = 218). Early pancreas allograft loss occurred in 12.8% (n = 28) of recipients. Delayed graft function (DGF) was more common (21.4% vs. 7.4%, p = 0.03) in the early pancreas loss group, but there were no differences in hospital length of stay (median 6.5 vs. 7.0, p = 0.22), surgical wound complications (p = 0.12), or rejection episodes occurring in the first year (p = 0.87). Despite differences in DGF, both groups had excellent renal function at 1 year post-transplant (eGFR 64.1 ± 20.8 vs. 65.8 ± 22.9, p = 0.75). There were no differences in patient (HR 0.58, 95% CI 0.18-1.87, p = 0.26) or kidney allograft survival (HR 0.84, 95% CI 0.23-3.06, p = 0.77). One- and 2-year protocol kidney biopsies were comparable between the groups and showed minimal chronic changes; the early pancreas loss group showed more cv changes at 2 years (p = 0.04). Current data demonstrate good outcomes and excellent kidney allograft function following early pancreas loss.

Hospitalizations for Cardiovascular Disease After Liver Transplantation in the United States.

Cardiovascular disease (CVD) is a leading cause of post-liver transplant death, and variable care patterns may affect outcomes. We aimed to describe epidemiology and outcomes of inpatient CVD care across US hospitals. Using a merged data set from the 2002-2011 Nationwide Inpatient Sample and the American Hospital Association Annual Survey, we evaluated liver transplant patients admitted primarily with myocardial infarction (MI), stroke (cerebrovascular accident [CVA]), congestive heart failure (CHF), dysrhythmias, cardiac arrest (CA), or malignant hypertension. Patient-level data include demographics, Charlson comorbidity index, and CVD diagnoses. Facility-level variables included ownership status, payer-mix, hospital resources, teaching status, and physician/nursing-to-bed ratios. We used generalized estimating equations to evaluate patient- and hospital-level factors associated with mortality. There were 4763 hospitalizations that occurred in 153 facilities (transplant hospitals, n = 80). CVD hospitalizations increased overall by 115% over the decade (P < 0.01). CVA and MI declined over time (both P < 0.05), but CHF and dysrhythmia grew significantly (both P < 0.03); a total of 19% of hospitalizations were for multiple CVD diagnoses. Transplant hospitals had lower comorbidity patients (P < 0.001) and greater resource intensity including presence of cardiac intensive care unit, interventional radiology, operating rooms, teaching status, and nursing density (all P < 0.01). Transplant and nontransplant hospitals had similar unadjusted mortality (overall, 3.9%, P = 0.55; by diagnosis, all P > 0.07). Transplant hospitals had significantly longer overall length of stay, higher total costs, and more high-cost hospitalizations (all P < 0.05). After risk adjustment, transplant hospitals were associated with higher mortality and high-cost hospitalizations. In conclusion, CVD after liver transplant is evolving and responsible for growing rates of inpatient care. Transplant hospitals are associated with poor outcomes, even after risk adjustment for patient and hospital characteristics, which may be attributable to selective referral of certain patient phenotypes but could also be related to differences in quality of care. Further study is warranted.

Glucose homeostasis after simultaneous pancreas and kidney transplantation: a comparison of subjects with C-peptide-positive non-type 1 diabetes mellitus and type 1 diabetes mellitus.

BACKGROUND: While simultaneous pancreas kidney transplant (SPKTx) is a therapeutic option for patients with type 1 diabetes (T1DM) and renal failure, few centers offer SPKTx to "select" non-T1DM patients. To address concerns that existing insulin resistance may limit the benefits of the pancreas allograft among non-T1DM, we compared several indices of glucose homeostasis, in "select" non-T1DM and T1DM patients who received SPKTx. METHODS: Criteria for "select" non-T1DM included the following: positive C-peptide, BMI <30 kg/m(2) , treatment with oral agents before insulin initiation, and insulin at <1 unit/kg/d. We compared several indices of glucose homeostasis within 1 yr post-SPKTx among seven "select" patients with non-T1DM and nine patients with T1DM with similar age, BMI, and immunosuppression. Measurements of insulin resistance included the following: homeostatic model, insulin sensitivity index, and insulin-glucose ratio; insulin secretion measures included the following: corrected insulin response. RESULTS: Non-T1DM had similar pre-transplant metabolic (fasting glucose, HbA1c, blood pressure, and lipid) parameters to the T1DM cohort. There were no significant differences in the various measures of insulin resistance and secretion between T1DM and "select" non-T1DM patients. CONCLUSION: Our results suggest SPKTx should be considered in the therapeutic armamentarium among carefully select non-T1DM with features of minimal insulin resistance; however, a larger cohort with longer follow-up is needed to confirm our results.

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.).

Declining Medicare reimbursement in abdominal transplantation from 2000 to 2021.

BACKGROUND: The Centers for Medicare and Medicaid Services is a major payer for abdominal transplant services. Reimbursement reductions could have a major impact on the transplant surgical workforce and hospitals. Yet government reimbursement trends in abdominal transplantation have not been fully characterized. METHODS: We performed an economic analysis to characterize changes in inflation-adjusted trends in Medicare surgical reimbursement for abdominal transplant procedures. Using the Medicare Fee Schedule Look-Up Tool, we performed a procedure code-based surgical reimbursement rate analysis. Reimbursement rates were adjusted for inflation to calculate overall changes in reimbursement, overall year-over-year, 5-year year-over-year, and compound annual growth rate from 2000 to 2021. RESULTS: We observed declines in adjusted reimbursement of common abdominal transplant procedures, including liver (-32.4%), kidney with and without nephrectomy (-24.2% and -24.1%, respectively), and pancreas transplant (-15.2%) (all, P < .05). Overall, the yearly average change for liver, kidney with and without nephrectomy, and pancreas transplant were -1.54%, -1.15%, -1.15%, and -0.72%. Five-year annual change averaged -2.69%, -2.35%, -2.64%, and -2.43%, respectively. The overall average compound annual growth rate was -1.27%. CONCLUSION: This analysis depicts a worrisome reimbursement pattern for abdominal transplant procedures. Transplant surgeons, centers, and professional organizations should note these trends to advocate sustainable reimbursement policy and to preserve continued access to transplant services.

Pregnancy outcomes of liver transplant recipients: a systematic review and meta-analysis.

Approximately 14,000 women of reproductive age are currently living in the United States after liver transplantation (LT), and another 500 undergo LT each year. Although LT improves reproductive function in women with advanced liver disease, the associated pregnancy outcomes and maternal-fetal risks have not been quantified in a broad manner. To obtain more generalizable inferences, we performed a systematic review and meta-analysis of articles that were published between 2000 and 2011 and reported pregnancy-related outcomes for LT recipients. Eight of 578 unique studies met the inclusion criteria, and these studies represented 450 pregnancies in 306 LT recipients. The post-LT live birth rate [76.9%, 95% confidence interval (CI) = 72.7%-80.7%] was higher than the live birth rate for the US general population (66.7%) but was similar to the post-kidney transplantation (KT) live birth rate (73.5%). The post-LT miscarriage rate (15.6%, 95% CI = 12.3%-19.2%) was lower than the miscarriage rate for the general population (17.1%) but was similar to the post-KT miscarriage rate (14.0%). The rates of pre-eclampsia (21.9%, 95% CI = 17.7%-26.4%), cesarean section delivery (44.6%, 95% CI = 39.2%-50.1%), and preterm delivery (39.4%, 95% CI = 33.1%-46.0%) were higher than the rates for the US general population (3.8%, 31.9%, and 12.5%, respectively) but lower than the post-KT rates (27.0%, 56.9%, and 45.6%, respectively). Both the mean gestational age and the mean birth weight were significantly greater (P < 0.001) for LT recipients versus KT recipients (36.5 versus 35.6 weeks and 2866 versus 2420 g). Although pregnancy after LT is feasible, the complication rates are relatively high and should be considered during patient counseling and clinical decision making. More case and center reports are necessary so that information on post-LT pregnancy outcomes and complications can be gathered to improve the clinical management of pregnant LT recipients. Continued reporting to active registries is highly encouraged at the center level.

Utilization of Veno-Arterial Extracorporeal Life Support for Acute Respiratory Distress Syndrome After Liver Transplant.

In this report, we present a case of successful long-term salvage of a patient with transfusion-related acute lung injury associated with acute respiratory distress syndrome immediately after a liver transplant. The patient was a 29-year-old man with end-stage liver disease due to sclerosing cholangitis who underwent liver transplant. After organ reperfusion, there was evidence of liver congestion, acidosis, coagulopathy, and acute kidney injury. He received 61 units of blood products. Continuous renal replacement therapy was initiated intraoperatively. On arrival to the intensive care unit, the patient was on high-dose pressors, and the patient developed respiratory failure and was immediately placed on veno-arterial extracorporeal membrane oxygenation via open femoral exposure. The patient presented with severe coagulopathy and early allograft dysfunction; therefore, no systemic heparin was administered and no thrombotic events occurred. He required extracorporeal membrane oxygenation support until posttransplant day 4, when resolution of the respiratory and cardiac dysfunction was noted. At 2 years after liver transplant, the patient has normal liver function, normal cognitive function, and stage V chronic kidney disease. We conclude that extracorporeal membrane oxygenation is a valuable therapeutic approach in patients with cardiorespiratory failure after liver transplant.

High infectious risk donors: what are the risks and when are they too high?

PURPOSE OF REVIEW: High infectious risk donors (HRDs) fall into a behavioral category thought to increase risk of infectious transmission through transplantation; despite controversy surrounding their use, they comprise almost 9% of donors in which at least one organ is recovered. This review seeks to describe national patterns in utilization, attitudes toward HRDs, and strategies to minimize and quantify infectious risks. RECENT FINDINGS: HRD organs are discarded at a higher rate than non-HRDs, and many surgeons have decreased the use of HRDs in response to a recent widely publicized case of HIV and hepatitis C virus (HCV) transmission. Special informed consent use can mitigate legal risk and might increase provider comfort with HRD utilization. Nucleic acid testing (NAT) mitigates infectious risk by decreasing the window period, particularly for HCV in which the risk of undetected window period infection decreases by an order of magnitude. Estimated risk of undetected window period HIV infection varies by HRD behavior category (range 0.035-4.9 per 10,000 donors when NAT is used), HCV risk is higher (range 0.027-32.4 per 10.000). SUMMARY: Given long waiting times and high waitlist mortality, organs from HRDs can be used to expand the organ supply. Estimates of HRD infectious risk can be used to guide patient and provider decision making.

Liver Transplant in a Polymerase Chain Reaction-Positive COVID-19 Recipient: A Case Report.

The severe acute respiratory syndrome coronavirus 2 coronavirus disease 2019 (COVID-19) global pandemic has ushered in an era of hesitation in performing transplants in affected patients. This stems from the paucity of data regarding the testing modalities, long-term implications, and uncertain prognosis in this group of patients. Current guidance from the Centers for Disease Control recommends assessing symptoms rather than polymerase chain reaction (PCR) positivity. In light of these recommendations, we describe a case of an orthotopic liver transplant in a patient infected with COVID-19 with persistent PCR positivity for 40 days before retransplant. The patient's perioperative and postoperative course was uncomplicated. Our experience leads us to advocate for liver transplants in patients who are PCR positive for COVID-19 after careful individualized and multidisciplinary evaluation regarding their liver disease and COVID-19 symptomatology.

Overcoming Mismatch Concerns for Adult Recipients of Small Pediatric Deceased Donor Kidneys.

BACKGROUND: Kidneys from very young pediatric donors continue to be underutilized. To reduce discard, the Organ Procurement and Transplantation Network (OPTN) policy was recently updated to allow kidneys from donors weighing <18 kg to be recovered en bloc. METHODS: We reviewed our center's experience with kidney transplantation in adult recipients of <18 kg pediatric donor kidneys to assess renal function outcomes specific to solitary vs en bloc usage. RESULTS: The majority of <18 kg donors were used en bloc (n = 39, 72.2% vs n = 15, 27.8%). Donor weight (kg) was similar between the 2 groups (12.3 ± 3.2 vs 14.1 ± 2.5, P = .05). Recipient weight was lower in the solitary kidney group (P = .01). Both groups had a similar donor-to-recipient body weight ratio (0.24 ± 0.3 vs 0.18 ± 0.3, P = .51). The solitary kidney group had a lower estimated glomerular filtration rate at 1 (56.9 ± 24.3 vs 81.8 ± 24.8, P = .01) and 2 years (72 ± 18.6 vs 93.7 ± 21.6, P = .03). By 2 years, both groups had an average estimated glomerular filtration rate >60 mL/min. Kidney allograft growth occurred in both groups, with the largest increase occurring the first month posttransplant (11.9%, 18.6%, P < .0001). CONCLUSION: For pediatric donors weighing <18 kg, improvements in renal function continue beyond the first posttransplant year. Risk for hyperfiltration injury appears low and renal mass-recipient mass matching is useful in guiding decision-making for solitary vs en bloc utilization.

Perioperative mortality and long-term survival following live kidney donation.

CONTEXT: More than 6000 healthy US individuals every year undergo nephrectomy for the purposes of live donation; however, safety remains in question because longitudinal outcome studies have occurred at single centers with limited generalizability. OBJECTIVES: To study national trends in live kidney donor selection and outcome, to estimate short-term operative risk in various strata of live donors, and to compare long-term death rates with a matched cohort of nondonors who are as similar to the donor cohort as possible and as free as possible from contraindications to live donation. DESIGN, SETTING, AND PARTICIPANTS: Live donors were drawn from a mandated national registry of 80 347 live kidney donors in the United States between April 1, 1994, and March 31, 2009. Median (interquartile range) follow-up was 6.3 (3.2-9.8) years. A matched cohort was drawn from 9364 participants of the third National Health and Nutrition Examination Survey (NHANES III) after excluding those with contraindications to kidney donation. MAIN OUTCOME MEASURES: Surgical mortality and long-term survival. RESULTS: There were 25 deaths within 90 days of live kidney donation during the study period. Surgical mortality from live kidney donation was 3.1 per 10,000 donors (95% confidence interval [CI], 2.0-4.6) and did not change during the last 15 years despite differences in practice and selection. Surgical mortality was higher in men than in women (5.1 vs 1.7 per 10,000 donors; risk ratio [RR], 3.0; 95% CI, 1.3-6.9; P = .007), in black vs white and Hispanic individuals (7.6 vs 2.6 and 2.0 per 10,000 donors; RR, 3.1; 95% CI, 1.3-7.1; P = .01), and in donors with hypertension vs without hypertension (36.7 vs 1.3 per 10,000 donors; RR, 27.4; 95% CI, 5.0-149.5; P < .001). However, long-term risk of death was no higher for live donors than for age- and comorbidity-matched NHANES III participants for all patients and also stratified by age, sex, and race. CONCLUSION: Among a cohort of live kidney donors compared with a healthy matched cohort, the mortality rate was not significantly increased after a median of 6.3 years.

Robot Assisted Renal Allograft Nephrectomy: Initial Case Series and Description of Technique.

OBJECTIVE: To evaluate the outcomes and perioperative complication rates following robot- assisted transplant nephrectomy ((RATN). METHODS: All patients who underwent RATN at our institution were included. No exclusion criteria were applied. Clinical records were retrospectively reviewed and reported. This included preoperative, intraoperative, and postoperative outcomes. Complications were reported utilizing the Clavien-Dindo classification system. Descriptive statistics were reported using frequencies and percentages for categorical variables, means and standard deviation for continuous variables. RESULTS: Between July 2014 and April 2018, 15 patients underwent RATN. Most patients had the transplant in the right iliac fossa (13/15). Ten patients underwent a concomitant procedure. The total operative time for the entire cohort was 336 (±102) minutes (including cases who had concomitant procedures) and 259 (±46 minutes) when cases with concomitant procedures were excluded. Mean estimated blood loss was 383 (±444) mL. Postoperatively, 3 patients required blood transfusion. Average hospital stay was 4 (±2.7) days. Most patients had finding consistent with graft rejection on final pathology. There were 5 complications; 3 of which were minor (grade 2 = 2 and grade 3 = 1); one patient had a wound infection requiring dressing (3A) and one patient died due to pulmonary embolism following discharge. Limitations include small series and retrospective nature of the study. CONCLUSION: This case series demonstrate that RATN is technically feasible. With continued experience and larger case series, the robotic approach may provide a minimally invasive alternative to open allograft nephrectomy.

ABO-incompatible deceased donor liver transplantation in the United States: a national registry analysis.

In the United States, ABO-incompatible liver transplantation (ILT) is limited to emergent situations when ABO-compatible liver transplantation (CLT) is unavailable. We analyzed the United Network for Organ Sharing database of ILT performed from 1990-2006 to assess ILT outcomes for infant (0-1 years; N = 156), pediatric (2-17 years; N = 170), and adult (> 17 years; N = 667) patients. Since 2000, the number of ILT has decreased annually, and there has been decreased use of blood type B donors and increased use of blood type A donors. Furthermore, ILT graft survival has improved for all age groups in recent years, beyond the improved graft survival attributable to era effect based on comparison to respective age group CLT. On matched control analysis, graft survival was significantly worse for adult ILT as compared to adult CLT. However, infant and pediatric ILTs did not have worse graft survival versus age-matched CLT. Adjusted analyses identified age-specific characteristics impacting ILT graft loss. For infants, transplant after 2000 and donor age < 9 years were associated with reduced risk of ILT graft loss. For pediatric patients, female recipient sex and donor age > 50 years were associated with increased risk of ILT graft loss. For adults, life support, repeat transplant, split grafts, and hepatocellular carcinoma were associated with increased risk of ILT graft loss. The current study identifies important trends in ILT in the United States in the modern immunosuppression era, as well as specific recipient, donor, and graft characteristics impacting ILT graft survival that could be utilized to guide ILT organ allocation in exigent circumstances. Liver Transpl 15:883-893, 2009. (c) 2009 AASLD.

Successful liver transplantation for Budd-Chiari syndrome in a patient with paroxysmal nocturnal hemoglobinuria treated with the anti-complement antibody eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by somatic mutations in the phosphatidylinositol glycan-complementation class A gene and the resulting absence of a key complement regulatory protein, CD59. Affected red blood cells in patients with PNH undergo intravascular complement-mediated lysis with resulting anemia, hemoglobinuria, and venous thromboses. Hepatic venous outflow thrombosis [Budd-Chiari syndrome (BCS)] is especially common in PNH patients and often fatal. The few case reports of outcomes in patients undergoing liver transplant for BCS secondary to PNH detail instances of recurrent BCS as well as early thrombotic portal vein occlusion and hepatic artery thrombosis requiring retransplantation. PNH is therefore generally considered a contraindication to liver transplantation. Here we present the first report of a patient with PNH and BCS undergoing successful liver transplantation while receiving eculizumab, a humanized monoclonal antibody that blocks the activation of the terminal complement at C5.

Increased risk of graft loss from hepatic artery thrombosis after liver transplantation with older donors.

Hepatic artery thrombosis (HAT) is the most common vascular complication after liver transplantation; it has been reported to occur in 2% to 5% of liver transplant recipients. Most reports of HAT in the literature describe single-center series with small numbers of patients and lack the power to definitively identify nontechnical risk factors. We used the United Network for Organ Sharing database of adult deceased donor liver transplants from 1987 to 2006 to identify 1246 patients with graft loss from HAT. Univariate and multivariate regression analyses were performed to identify donor and graft risk factors for HAT-induced graft loss. Although most donor predictors of HAT-induced graft loss were surrogates for vessel size, donor age > 50 years was also a significant predictor of graft loss from HAT (relative risk = 1.45, P < 0.001). Furthermore, the risk of graft loss from HAT increased progressively with each decade of donor age > 50 years, such that a 61% increased risk of HAT-related graft loss (relative risk = 1.61, P < 0.001) was associated with donor age > 70 years. A separate analysis of risk factors for early HAT graft loss ( 90 days) found that older donor age was associated with increased late HAT graft loss. These findings are of interest in an era of ongoing organ shortages requiring maximum utilization of potential allografts and increasing allocation of older allografts.

Persistence of cooperatively stabilized signaling clusters drives T-cell activation.

Antigen recognition triggers the recruitment of the critical adaptor protein SLP-76 to small macromolecular clusters nucleated by the T-cell receptor (TCR). These structures develop rapidly, in parallel with TCR-induced increases in tyrosine phosphorylation and cytosolic calcium, and are likely to contribute to TCR-proximal signaling. Previously, we demonstrated that these SLP-76-containing clusters segregate from the TCR and move towards the center of the contact interface. Neither the function of these clusters nor the structural requirements governing their persistence have been examined extensively. Here we demonstrate that defects in cluster assembly and persistence are associated with defects in T-cell activation in the absence of Lck, ZAP-70, or LAT. Clusters persist normally in the absence of phospholipase C-gamma1, indicating that in the absence of a critical effector, these structures are insufficient to drive T-cell activation. Furthermore, we show that the critical adaptors LAT and Gads localize with SLP-76 in persistent clusters. Mutational analyses of LAT, Gads, and SLP-76 indicated that multiple domains within each of these proteins contribute to cluster persistence. These data indicate that multivalent cooperative interactions stabilize these persistent signaling clusters, which may correspond to the functional complexes predicted by kinetic proofreading models of T-cell activation.

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.

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.