Impact of Renal Replacement Therapy on Rejection among Liver Transplant Recipients.

Introduction: Renal dysfunction in liver transplant recipients is associated with an increased risk of morbidity and mortality, with an even higher risk among patients requiring renal replacement therapy. There is limited data evaluating rejection outcomes in patients requiring renal replacement therapy after liver transplant. Program evaluation aims: To evaluate the incidence of biopsy-proven acute rejection, recipient and graft survival, infection, renal dysfunction, and immunosuppression practices. Design: This was a single-center, retrospective, cohort study. To be eligible, patients were deceased donor liver transplant recipients ≥18 year of age transplanted between January 2017 and August 2019 who received steroid-only induction and tacrolimus as part of their initial immunosuppression regimen. Results: Recipients that required renal replacement therapy (N = 86) were compared to those who received no renal replacement therapy (N = 158). Biopsy-proven acute rejection at 1-year posttransplant was significantly higher among those requiring renal replacement therapy (36% vs 13%, P < .001). Patient survival at 12 months was 77% for those requiring renal replacement therapy and 94% for those not requiring renal replacement therapy (P < .001). Infection (HR 3.8, 95% CI 1.6-8.8; P < .001), but not rejection (HR 0.7, 95% CI 0.3-1.7; P = .5) was an independent predictor of mortality. The use of renal replacement therapy after liver transplant necessitated careful titration of immunosuppression to balance the detrimental risks of infection versus rejection in this high-risk population.

Digital imaging software versus the "eyeball" method in quantifying steatosis in a liver biopsy.

Steatotic livers represent a potentially underutilized resource to increase the donor graft pool; however, 1 barrier to the increased utilization of such grafts is the heterogeneity in the definition and the measurement of macrovesicular steatosis (MaS). Digital imaging software (DIS) may better standardize definitions to study posttransplant outcomes. Using HALO, a DIS, we analyzed 63 liver biopsies, from 3 transplant centers, transplanted between 2016 and 2018, and compared macrovesicular steatosis percentage (%MaS) as estimated by transplant center, donor hospital, and DIS. We also quantified the relationship between DIS characteristics and posttransplant outcomes using log-linear regression for peak aspartate aminotransferase, peak alanine aminotransferase, and total bilirubin on postoperative day 7, as well as logistic regression for early allograft dysfunction. Transplant centers and donor hospitals overestimated %MaS compared with DIS, with better agreement at lower %MaS and less agreement for higher %MaS. No DIS analyzed liver biopsies were calculated to be >20% %MaS; however, 40% of liver biopsies read by transplant center pathologists were read to be >30%. Percent MaS read by HALO was positively associated with peak aspartate aminotransferase (regression coefficient= 1.04 1.08 1.12 , p <0.001), peak alanine aminotransferase (regression coefficient = 1.04 1.08 1.12 , p <0.001), and early allograft dysfunction (OR= 1.10 1.40 1.78 , p =0.006). There was no association between HALO %MaS and total bilirubin on postoperative day 7 (regression coefficient = 0.99 1.01 1.04 , p =0.3). DIS provides reproducible quantification of steatosis that could standardize MaS definitions and identify phenotypes associated with good clinical outcomes to increase the utilization of steatite livers.

The Impact of Treatment Delay on Hepatitis C Liver Transplant Outcomes.

Background: Direct-acting antivirals for the treatment of hepatitis C virus (HCV) have improved outcomes in liver transplant recipients (LTRs). However, the timing of HCV treatment and approach to treating rejection have not been well described. Additionally, pharmacists' roles in these comprehensive areas have not been investigated. Methods: This single-center, retrospective, cohort review compared 1-year graft and patient survival between HCV-positive and HCV-negative LTRs. Secondary endpoints included 1-year rejection rates, HCV sustained virologic response and time to HCV treatment. Results: Ninety-two HCV Nucleic Acid Amplification Test (NAT)-positive LTRs were matched 1:1 to HCV-seronegative LTRs. One-year graft and patient survival were similar between groups. HCV-positive LTRs were more likely to experience biopsy-proven acute rejection (BPAR), and despite treatment with pulse steroids, there was no impact on graft survival or occurrence of fibrosing cholestatic hepatitis (FCH). Time to HCV treatment was 5.4-6.4 months post-transplant, with no treatment failures or impact on graft or patient survival. Conclusions: No difference was seen in graft survival at 1 year between HCV-positive and HCV-seronegative LTRs. Delayed time to treatment of HCV and treatment of rejections in the HCV-positive cohort did not impact outcomes. However, pharmacist-driven protocols could ensure more efficient initiation of HCV treatment in the future.

COVID-19 in hospitalized liver transplant recipients: An early systematic review and meta-analysis.

Adverse clinical outcomes related to SARS-CoV-2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta-analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID-19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID-19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%-93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In-hospital mortality was 20% (95% CI, 13%-28%) and rose to 41% (95% CI, 19%-63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60-65 years) (OR 4.26; 95% CI, 2.14-8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID-19 had a high prevalence of dyspnea and gastrointestinal symptoms. In-hospital mortality was comparable to non-transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%-40%). Importantly, the observed high case fatality in the elderly could be due to age-associated comorbidities.

Vascularized Bone Marrow Cellular Depletion or Discontinuity Abrogates Protection of Vascularized Composite Allografts in Nonhuman Primates.

BACKGROUND: Vascularized composite allografts (VCA) have demonstrated good clinical outcomes dependent on chronic immunosuppression. Previous work by our group and others supports that cotransplanted vascularized bone marrow (VBM) as a component of VCA offers immunologic protection to prolong graft survival. We aimed to characterize the requirements and potential mechanisms of VBM-mediated protection of VCA by modifying grafts through various strategies. METHODS: Experimental groups of mismatched cynomolgus macaque recipients received VCA transplants modified by the following approaches: heterotopic separation of the VCA and VBM components; T-cell depletion of either donor or recipient; irradiation of donor VCA; and infusion of donor bone marrow. All groups received standard immunosuppression with tacrolimus and mycophenolate mofetil. RESULTS: Experimental modifications to donor, recipient, or graft all demonstrated short-graft survivals (31 d). Chimerism levels without bone marrow infusion were transient and minimal when detected and were not associated with prolonged survival. Donor bone marrow infusion increased levels of chimerism but resulted in alloantibody production and did not improve graft survival. CONCLUSIONS: VCA graft survival is significantly reduced compared with previously reported VCA with VBM transplants (348 d; P = 0.01) when the hematopoietic niche is removed, altered, or destroyed via irradiation, depletion, or topographical rearrangement. These experimental manipulations resulted in similar outcomes to VCA grafts without cotransplanted VBM (25 d). These data support the presence of a radiosensitive, T-cell population within the VBM compartment not reconstituted by reinfusion of bone marrow cells.

Successful Implementation of Unmanned Aircraft Use for Delivery of a Human Organ for Transplantation.

OBJECTIVE: To understand and overcome the challenges associated with moving life-urgent payloads using unmanned aircraft. BACKGROUND DATA: Organ transportation has not been substantially innovated in the last 60 years. Unmanned aircraft systems (UAS; ie, drones) have the potential to reduce system inefficiencies and improve access to transplantation. We sought to determine if UASs could successfully be integrated into the current system of organ delivery. METHODS: A multi-disciplinary team was convened to design and build an unmanned aircraft to autonomously carry a human organ. A kidney transplant recipient was enrolled to receive a drone-shipped kidney. RESULTS: A uniquely designed organ drone was built. The aircraft was flown 44 times (total of 7.38 hours). Three experimental missions were then flown in Baltimore City over 2.8 miles. For mission #1, no payload was carried. In mission #2, a payload of ice, saline, and blood tubes (3.8 kg, 8.4 lbs) was flown. In mission #3, a human kidney for transplant (4.4 kg, 9.7 lbs) was successfully flown by a UAS. The organ was transplanted into a 44-year-old female with a history of hypertensive nephrosclerosis and anuria on dialysis for 8 years. Between postoperative days (POD) 1 and 4, urine increased from 1.0 L to 3.6 L. Creatinine decreased starting on POD 3, to an inpatient nadir of 6.9 mg/dL. The patient was discharged on POD 4. CONCLUSIONS: Here, we completed the first successful delivery of a human organ using unmanned aircraft. This study brought together multidisciplinary resources to develop, build, and test the first organ drone system, through which we performed the first transplant of a drone transported kidney. These innovations could inform not just transplantation, but other areas of medicine requiring life-saving payload delivery as well.

Is Prophylactic Drainage After Pancreas Transplant Associated With Reduced Reoperation Rate?

OBJECTIVES: Advances in surgery and perioperative care have contributed to improved outcomes after pancreas transplant. However, the development of peripancreatic infections carries a poor prognosis. It is not clear whether abdominal drainage is helpful in collection prevention. MATERIALS AND METHODS: A retrospective review of adult consecutive pancreas transplants at a single institution between January 2017 and December 2018 was undertaken. Postoperative outcomes were compared between patients in whom prophylactic intraoperative drains were placed and patients with no drains. RESULTS: We identified 83 patients who underwent pancreas transplant with a median age of 45 years; 54.2% were males, and median body mass index was 25.8. Thirty patients had 1 or 2 drains placed (36.1%). There was no difference in the readmission rate (70.0% vs 60.4%; P = .48), reoperation (20.0% vs 30.2%; P = .44), or percutaneous drainage of peripancreatic infections (20.0% vs 15.1%; P = .56) between patients with drains and no drains, respectively. However, prophylactic drainage was associated with a lower rate of reoperation for peripancreatic infections compared with those who were not drained (0.0% vs 13.2%; P < .05). No graft loss occurred in the drain group. CONCLUSIONS: Prophylactic drainage after pancreas transplant may be helpful for reduction in the infection rate after reoperation. The risks of drain placement should be weighed against those of drain avoidance.

Endovascular Reconstruction of the Hepatic Arterial System for the Management of Mycotic Pseudoaneurysm in a Liver Transplant Patient.

BACKGROUND: Hepatic artery pseudoaneurysm is a rare but very morbid complication after liver transplant. Treatment options include ligation or endovascular embolization, followed by revascularization. We describe a new endovascular approach by stent exclusion in a high-risk patient. RESULTS: A 62-year-old male who received a second liver transplant after failed allograft presented with hemobilia and was diagnosed with a hepatic artery pseudoaneurysm in the setting of infection. Given his hostile abdomen, an endovascular approach was sought. We excluded the mycotic pseudoaneurysm with multiple covered stent grafts extending from the common hepatic artery to the right and left hepatic arteries. He was discharged with long-term antibiotics. On his 6-month follow-up visit, his stent was patent and hepatic function was stable. CONCLUSIONS: Endovascular stent-graft placement for management of hepatic artery pseudoaneurysm after liver transplant should be considered as a lower morbidity alternative to surgical repair, even in the setting of infection.

Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts.

We performed a prospective, 12-month, single-center, nonrandomized, open-label pilot study to investigate the use of belatacept therapy combined with alemtuzumab induction in renal allografts with preexisting pathology, as these kidneys may be more susceptible to additional toxicity when exposed to calcineurin inhibitors posttransplant. Nineteen belatacept recipients were matched retrospectively to a cohort of tacrolimus recipients on the basis of preimplantation pathology. The estimated glomerular filtration rate was not significantly different between belatacept and tacrolimus recipients at either 3 or 12 months posttransplant (59 vs 45, P = 0.1 and 56 vs 48 mL/min/1.72/m2 , P = 0.3). Biopsy-proven acute rejection rates at 12 months were 26% in belatacept recipients and 16% in tacrolimus recipients (P = 0.7). Graft survival at 1 year was 89% in both groups. Alemtuzumab induction combined with either calcineurin inhibitor or costimulatory blockade therapies resulted in similar acceptable one-year outcomes in kidneys with preexisting pathologic changes. Longer-term follow-up may be necessary to identify preferential strategies to improve outcomes of kidneys at a higher risk for poor function (ClinicalTrials.gov-NCT01496417).

Diabetic nephropathy after kidney transplantation in patients with pretransplantation type II diabetes: A retrospective case series study from a high-volume center in the United States.

BACKGROUND: Patients with type II diabetes mellitus (DM) undergoing renal transplantation are at risk of diabetic nephropathy (DN) in the transplanted kidney. The true risk of developing post-transplantation DN is unknown, and post-transplantation DN is poorly characterized in the literature. METHODS: The biopsy database at the University of Maryland Medical Center was queried for kidney transplant biopsies which demonstrated evidence of DN. The time from transplantation to biopsy-proven DN (time to diagnosis, TTD) was calculated and analyzed in the context of demographics, serum creatinine, and onset of diabetes. By extrapolating the total number of patients who developed DN in the last 2 years, we estimated the recurrence rate of DN. RESULTS: Sixty patients whose renal biopsies met criteria were identified. The mean age was 56.6 (±1.58) years, and the mean creatinine level at time of biopsy was 1.65 (±0.12) mg/dL. Simultaneous pathological diagnoses were frequent on kidney biopsy; rejection was present at variable rates: classes I, IIA, IIB, and III were 5.0%, 66.7%, 18.4%, and 10%, respectively. The mean TTD was 1456 (±206) days. TTD was significantly shorter for patients receiving a cadaveric vs living donor renal transplant (1118 ± 184 vs 2470 ± 547 days, P = 0.004). Older patients (r = 0.378, P = 0.003) and patients with higher serum creatinine (r = 0.282, P = 0.029) had shorter TTDs. Extrapolations showed that 74.7% of patients would be free of DN 10 years after renal transplantation. CONCLUSIONS: Diabetic nephropathy occurs after transplantation, and this appears to be due to both donor and recipient-derived factors. Encouragingly, our estimates suggest that as many as 75% of patients may be free of DN at 10 years following kidney transplantation.

Minimally invasive donor nephrectomy: current state of the art.

BACKGROUND: The concept of a minimally invasive live donor nephrectomy developed over 20 years ago. Surgeons gained expertise with the laparoscopic technique and utilized multiple variations that are now utilized in transplant centers throughout the world. Recent modifications include laparoendoscopic single-site and robotic approaches that have been adopted by an additional smaller set of programs. PURPOSE: Review was performed of the following eight different surgical approaches to a "minimally invasive" live donor nephrectomy: laparoscopic (LDN), hand-assisted laparoscopic (HALDN), retroperitoneoscopic (RLDN), hand-assisted retroperitoneoscopic (HARS), single-port laparoscopic (LESS), robotic-assisted laparoscopic (RALDN), mini open, and natural orifice transluminal endoscopic (NOTES). The techniques are described and summaries of available outcomes and complications are presented. CONCLUSIONS: Traditional surgical techniques of open donor nephrectomy have transitioned to minimally invasive techniques. With adoption of these techniques as the preferred approach, several variations have and continue to evolve. The current minimally invasive donor nephrectomy techniques share low complication rates and excellent outcomes.

Robotic-assisted single-port donor nephrectomy using the da Vinci single-site platform.

BACKGROUND: Although single-port donor nephrectomy offers improved cosmetic outcomes, technical challenges have limited its application to selected centers. Our center has performed over 400 single-port donor nephrectomies. The da Vinci single-site robotic platform was utilized in an effort to overcome the steric, visualization, ergonomic, and other technical limitations associated with the single-port approach. MATERIALS AND METHODS: Food and Drug Administration device exemption was obtained. Selection criteria for kidney donation included body mass index <35, left kidney donors, and ≤2 renal arteries. After colonic mobilization using standard single-port techniques, the robotic approach was utilized for ureteral complex and hilar dissection. RESULTS: Three cases were performed using the robotic single-site platform. Average total operative time was 262 ±â€¯42 min including 82 ±â€¯16 min of robotic use. Docking time took 20 ±â€¯10 min. Blood loss averaged 77 ±â€¯64 mL. No intraoperative complications occurred, and all procedures were completed with our standard laparoscopic single-port approach. CONCLUSIONS: This is the first clinical experience of robotic-assisted donor nephrectomy utilizing the da Vinci single-site platform. Our experience supported the safety of this approach but found that the technology added cost and complexity without tangible benefit. Development of articulating instruments, energy, and stapling devices will be necessary for increased application of robotic single-site surgery for donor nephrectomy.

Molecular Adsorbent Recirculating System Effectively Replaces Hepatic Function in Severe Acute Liver Failure.

BACKGROUND DATA: Patients with severe acute liver failure (ALF) have extreme physiologic dysfunction and often die if transplantation is not immediately available. Patients may be supported with MARS (Baxter International Inc., Deerfield, IL) until transplantation or spontaneous recovery occurs. We present the largest series in the United States of MARS therapy as temporary hepatic replacement for ALF. METHODS: MARS was used to support patients with severe liver trauma (SLT), in ALF patients as a bridge to transplantation (BTT), and as definitive therapy for toxic ingestion or idiopathic liver failure (DT) in a level 1 trauma center and large transplant center. Patient demographics, etiology of ALF, and laboratory values were recorded. Endpoints were patient survival ± liver transplant and/or recovery of liver function. RESULTS: Twenty-seven patients with severe ALF received MARS therapy. Five patients with SLT had a 60% survival with recovery of liver and renal function. Thirteen patients received MARS as a BTT, of which 9 were transplanted with a 1-year survival of 78% (program overall survival 85% at 1 year). All 4 who were not transplanted expired. Nine patients with ALF from toxic ingestion received MARS as DT with liver recovery and survival in 67%. MARS therapy resulted in significant improvement in liver function, coagulation, incidence of encephalopathy, and creatinine. CONCLUSIONS: MARS therapy successfully replaced hepatic function in ALF allowing time for spontaneous recovery or transplantation. Spontaneous recovery was remarkably common if support can be sustained.

Surgical complications of laparoendoscopic single-site donor nephrectomy: a retrospective study.

The single-port approach has been associated with an unacceptably high rate of umbilical port hernias in large series of patients undergoing single-port cholecystectomy and colectomy and with additional surgical risks thought secondary to technical and ergonomic limitations. A retrospective review of 378 consecutive laparoendoscopic single-site(LESS) donor nephrectomies performed between 04/15/2009 and 04/09/2014 was conducted. Twelve patients (3%) developed an umbilical hernia. Eleven (92%) were female and eight (73%) of these patients had a prior pregnancy. Hernias were reported 13.5 ± 6.9 months after donation, and the mean size was 5.1 ± 3.7 cm. Seven additional cases (1.9%) required a return to the operating room for internal hernia (2), evisceration (1), bleeding (1), enterotomy (1), and wound infection (2). The original incision was utilized for reexploration. One patient required emergent conversion to an open procedure for bleeding during the initial donation. There were no mortalities. Recipient patient and graft survival were 99% and 99% at 1 year, respectively. Although reports associated with earlier experiences with single-site procedures suggested an unacceptably high rate of hernias at the surgical site, this does not seem to be the case at our center. This technique is a reliable surgical technique for left donor nephrectomy at this institution.

Resolution of donor non-alcoholic fatty liver disease following liver transplantation.

INTRODUCTION: Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non-function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes. METHODS: Twenty-nine cases were identified with liver biopsies available from both the donor and the corresponding liver transplant recipient. Donor liver biopsies displayed either MaS or MiS ≥15%, while all recipients received postoperative liver biopsies for cause. RESULTS: The mean donor MaS and MiS were 15.6% (range 0%-60%) and 41.3% (7.5%-97.5%), respectively. MaS decreased significantly from donor (M=15.6%) to recipient postoperative biopsies (M=0.86%), P<.001. Similarly, MiS decreased significantly from donor biopsies (M=41.3%) to recipient postoperative biopsies (M=1.8%), P<.001. At a median of 68 days postoperatively (range 4-384), full resolution of MaS and MiS was observed in 27 of 29 recipients. CONCLUSIONS: High degrees of MaS and MiS in donor livers resolve in recipients following liver transplantation. Further insight into the mechanisms responsible for treating fatty liver diseases could translate into therapeutic targets.

Recellularization via the bile duct supports functional allogenic and xenogenic cell growth on a decellularized rat liver scaffold.

Recent years have seen a proliferation of methods leading to successful organ decellularization. In this experiment we examine the feasibility of a decellularized liver construct to support growth of functional multilineage cells. Bio-chamber systems were used to perfuse adult rat livers with 0.1% SDS for 24 hours yielding decellularized liver scaffolds. Initially, we recellularized liver scaffolds using a human tumor cell line (HepG2, introduced via the bile duct). Subsequent studies were performed using either human tumor cells co-cultured with human umbilical vein endothelial cells (HUVECs, introduced via the portal vein) or rat neonatal cell slurry (introduced via the bile duct). Bio-chambers were used to circulate oxygenated growth medium via the portal vein at 37C for 5-7 days. Human HepG2 cells grew readily on the scaffold (n = 20). HepG2 cells co-cultured with HUVECs demonstrated viable human endothelial lining with concurrent hepatocyte growth (n = 10). In the series of neonatal cell slurry infusion (n = 10), distinct foci of neonatal hepatocytes were observed to repopulate the parenchyma of the scaffold. The presence of cholangiocytes was verified by CK-7 positivity. Quantitative albumin measurement from the grafts showed increasing albumin levels after seven days of perfusion. Graft albumin production was higher than that observed in traditional cell culture. This data shows that rat liver scaffolds support human cell ingrowth. The scaffold likewise supported the engraftment and survival of neonatal rat liver cell slurry. Recellularization of liver scaffolds thus presents a promising model for functional liver engineering.

Vascularized Composite Allotransplantation: Medical Complications.

The objective of this review is to summarize the collective knowledge regarding the risks and complications in vascularized composite tissue allotransplantation (VCA), focusing on upper extremity and facial transplantation. The field of VCA has entered its second decade with an increasing experience in both the impressive good outcomes, as well as defining challenges, risks, and experienced poor results. The limited and selective publishing of negative outcomes in this relatively new field makes it difficult to conclusively evaluate outcomes of graft and patient survival and morbidities. Therefore, published data, conference proceedings, and communications were summarized in an attempt to provide a current outline of complications. These data on the medical complications of VCA should allow for precautions to avoid poor outcomes, data to better provide informed consent to potential recipients, and result in improvements in graft and patient outcomes as VCA finds a place as a therapeutic option for selected patients.

Live Donor Renal Transplant With Simultaneous Bilateral Nephrectomy for Autosomal Dominant Polycystic Kidney Disease Is Feasible and Satisfactory at Long-term Follow-up.

BACKGROUND: Timing of bilateral nephrectomy (BN) is controversial in patients with refractory symptoms of autosomal dominant polycystic kidney disease (APKD) in need of a renal transplant. METHODS: Adults who underwent live donor renal transplant (LRT) + simultaneous BN (SBN) from August 2003 to 2013 at a single transplant center (n = 66) were retrospectively compared to a matched group of APKD patients who underwent LRT alone (n = 52). All patients received general health and polycystic kidney symptom surveys. RESULTS: Simultaneous BN increased operative duration, estimated blood loss, transfusions, intravenous fluid, and hospital length of stay. Most common indications for BN were pain, loss of abdominal domain, and early satiety. There were more intraoperative complications for LRT + SBN (6 vs 0, P = 0.03; 2 vascular, 2 splenic, and 1 liver injury; 1 reexploration to adjust graft positioning). There were no differences in Clavien-Dindo grade I or II (39% vs 25%, P = 0.12) or grade III or IV (7.5% vs 5.7%, P = 1.0) complications during the hospital course. There were no surgery-related mortalities. There were no differences in readmission rates (68% vs 48%, P = 0.19) or readmissions requiring procedures (25% vs. 20%, P = 0.51) over 12 months. One hundred percent of LRT + SBN allografts functioned at longer than 1 year for those available for follow-up. Survey response rate was 40% for LRT-alone and 56% for LRT + SBN. One hundred percent of LRT + SBN survey responders were satisfied with their choice of having BN done simultaneously. CONCLUSIONS: Excellent outcomes for graft survival, satisfaction, and morbidity suggest that the combined operative approach be preferred for patients with symptomatic APKD to avoid multiple procedures, dialysis, and costs of staged operations.

Inhibiting CARD11 translation during BCR activation by targeting the eIF4A RNA helicase.

Human diffuse large B-cell lymphomas (DLBCLs) often aberrantly express oncogenes that generally contain complex secondary structures in their 5' untranslated region (UTR). Oncogenes with complex 5'UTRs require enhanced eIF4A RNA helicase activity for translation. PDCD4 inhibits eIF4A, and PDCD4 knockout mice have a high penetrance for B-cell lymphomas. Here, we show that on B-cell receptor (BCR)-mediated p70s6K activation, PDCD4 is degraded, and eIF4A activity is greatly enhanced. We identified a subset of genes involved in BCR signaling, including CARD11, BCL10, and MALT1, that have complex 5'UTRs and encode proteins with short half-lives. Expression of these known oncogenic proteins is enhanced on BCR activation and is attenuated by the eIF4A inhibitor Silvestrol. Antigen-experienced immunoglobulin (Ig)G(+) splenic B cells, from which most DLBCLs are derived, have higher levels of eIF4A cap-binding activity and protein translation than IgM(+) B cells. Our results suggest that eIF4A-mediated enhancement of oncogene translation may be a critical component for lymphoma progression, and specific targeting of eIF4A may be an attractive therapeutic approach in the management of human B-cell lymphomas.