High levels of donor-derived cell-free DNA in a case of graft-versus-host-disease following liver transplantation.

The diagnosis of graft-versus-host-disease (GVHD) after solid organ transplantation is made difficult by its variable clinical presentation and lack of sensitive and specific biomarkers to evaluate the immune state of transplant recipients. Emerging noninvasive diagnostic techniques like the quantification of donor-derived cell-free DNA (dd-cfDNA) for surveillance may improve the current standard-of-care. Herein, we report the use of this methodology in a patient with GVHD and corresponding levels of dd-cfDNA without any evidence of graft injury. Correlation of dd-cfDNA levels with the clinical course and its novel application here could lead to improvements in the rapid diagnosis of GVHD and in monitoring of response to treatment.

Impact of the acuity circle model for liver allocation on multivisceral transplant candidates.

Liver allocation was updated on February 4, 2020, replacing a Donor Service Area (DSA) with acuity circles (AC). The impact on waitlist outcomes for patients listed for combined liver-intestine transplantation (multivisceral transplantation [MVT]) remains unknown. The Organ Procurement and Transplantation Network/United Network for Organ Sharing database was used to identify all candidates listed for both liver and intestine between January 1, 2018 and March 5, 2021. Two eras were defined: pre-AC (2018-2020) and post-AC (2020-2021). Outcomes included 90-day waitlist mortality and transplant probability. A total of 127 adult and 104 pediatric MVT listings were identified. In adults, the 90-day waitlist mortality was not statistically significantly different, but transplant probability was lower post-AC. After risk-adjustment, post-AC was associated with a higher albeit not statistically significantly different mortality hazard (sub-distribution hazard ratio[sHR]: 8.45, 95% CI: 0.96-74.05; p = .054), but a significantly lower transplant probability (sHR: 0.33, 95% CI: 0.15-0.75; p = .008). For pediatric patients, waitlist mortality and transplant probability were similar between eras. The proportion of patients who underwent transplant with exception points was lower post-AC both in adult (44% to 9%; p = .04) and pediatric recipients (65% to 15%; p = .002). A lower transplant probability observed in adults listed for MVT may ultimately result in increased waitlist mortality. Efforts should be taken to ensure equitable organ allocation in this vulnerable patient population.

Ex Vivo Liver Resection and Autotransplantation: Should It be Used More Frequently?

OBJECTIVE: We herein advocate for more extensive utilization of ex vivo resection techniques for otherwise unresectable liver tumors by presenting the largest collective American experience. BACKGROUND: Advanced in situ resection and vascular reconstruction techniques have made R0 resection possible for otherwise unresectable liver tumors. Ex vivo liver resection may further expand the limits of resectability but remains underutilized due to concerns about technical complexity and vascular thrombosis. However, we believe that the skillset required for ex vivo liver resection is more widespread and the complications less severe than widely assumed, making ex vivo resection a more attractive option in selected case. METHODS: We retrospectively analyzed 35 cases performed by surgical teams experienced with ex vivo liver resections (at least 4 cases) between 1997 and 2021. RESULTS: We categorized malignancies as highly aggressive (n=18), moderately aggressive (n=14), and low grade (n=3). All patients underwent total hepatectomy, vascular reconstruction and resection in hypothermia on the backtable, and partial liver autotransplantation. Overall survival was 67%/39%/28%, at 1/3/5 years, respectively, with a median survival of 710 days (range: 22-4824). Patient survival for highly aggressive, moderately aggressive, and low-grade tumors was 61%/33%/23%, 67%/40%/22%, and 100%/100%/100% at 1/3/5 years, respectively, with median survival 577 days (range: 22-3873), 444 days (range: 22-4824), and 1825 days (range: 868-3549). CONCLUSIONS: Ex vivo resection utilizes techniques commonly practiced in partial liver transplantation, and we demonstrate relatively favorable outcomes in our large collective experience. Therefore, we propose that more liberal use of this technique may benefit selected patients in centers experienced with partial liver transplantation.

Machine perfusion organ preservation: Highlights from the American Transplant Congress 2021.

The American Transplant Congress 2021 was a virtual meeting and occurred between June 4 and June 9 through an online platform. We highlighted abstracts discussing machine perfusion preservation, a hot topic that may become the gold standard of organ preservation in the future. A total of 33 abstracts on organ machine preservation (3 for heart, 4 for lungs, 18 for liver, and 8 for kidneys) were presented at the meeting. We selected 23 abstracts that showed advances including new approaches to organ preservation, promising treatments and biomarkers, cellular therapy, and novel research areas. Here, we summarize the new developments concerning machine perfusion in both experimental and clinical studies.

En-Bloc Simultaneous Heart-Liver Transplantation in Adult Patients.

INTRODUCTION: Complexity of combined heart-liver transplantation has resulted in low adoption rates. We report a case series of adult patients receiving en-bloc heart-liver transplantation (HLTx), describe technical aspects, and discuss benefits of the technique. METHODS: Retrospective review of patients receiving en-bloc HLTx over 18 months, with clinical follow up to 1 year. Primary outcomes included postoperative mortality and major complications. Secondary outcomes included 1-year survival, cardiac or hepatic allograft rejection, and infection. RESULTS: Five patients received en-bloc HLTx. Mean recipient age was 43 years (26-63), and 3 patients were male. Total operative time was 430 minutes (393-480), cold and warm ischemic times of 85 (32-136) and 37.5 (31-47) minutes. Hospital survival was 80%. One patient died on postoperative day 55 due to fungal sepsis. Major postoperative complications included prolonged mechanical ventilation in 2 of 5 patients (40%), and renal insufficiency requiring hemodialysis in 2 of 5 patients (40%). Among patients discharged from hospital 1-year survival was 100%, with no evidence of rejection or infectious complications. CONCLUSION: En-bloc HLTx technique is a safe and effective strategy, decreasing operative times, and allograft ischemic times, whereas offering protection of implanted allografts during early stages of reperfusion while patient is hemodynamically supported on cardiopulmonary bypass.

Clostridium difficile infection mimics intestinal acute cellular rejection in pediatric multivisceral transplant-A case series.

Clostridium difficile infection (CDI) is the most common health care-associated infection in the United States. Thirty-nine percent of intestinal transplant recipients may develop CDI. Induction of rejection has been reported as a rare event. To our knowledge, this will be the second report of an association between CDI and rejection in the literature. We describe our experience with four pediatric MVT recipients, three of whom on treatment of their CDI alone had resolution of biopsy findings of intestinal ACR. Our patients were males aged 2-5 years old who had their first CDI post-MVT occurring from 2 months to 15 months post-transplant. All first episodes of CDI were treated with a 10-14 day course of metronidazole with one additionally receiving vancomycin. All four recipients had recurrent CDI, and two recipients had septic shock as a manifestation of their CDI. Three recipients had biopsies showing mild rejection during episodes of CDI, and treatment of the CDI resulted in resolution of biopsy findings of rejection. Our case series suggests CDI may mimic ACR on intestinal biopsy. Treatment of rejection during active CDI carries the risk of over-suppression and worsening of CDI. Our experience has taught us that surveillance endoscopy for rejection may be deceiving during an active CDI, and if mild acute rejection is noted during active CDI, treatment of rejection can be safely delayed and potentially avoided.

Use of pediatric donor en bloc kidneys along with bladder segment in pediatric liver-kidney and multivisceral-kidney transplantation.

The combination of pediatric multivisceral and kidney transplantation leads to additional recipient risks due to the number of anastomoses and to the small sizes of donor structures. The inclusion of donor kidneys, ureters, and a bladder patch en bloc with multivisceral organs decreases the number and complexity of anastomoses and has not yet been reported. Four patients were transplanted in this fashion; three underwent multivisceral-kidney and one underwent liver-kidney transplantation. The first patient was a 3-year-old male with polycystic kidney disease and congenital hepatic fibrosis. The second was a 7-year-old female with complications from necrotizing enterocolitis. The third was a 12-month-old male with megacystis microcolon intestinal hypoperistalsis syndrome and secondary hydronephrosis, and the fourth was a 3-year-old male with multiple intestinal resections secondary to incarcerated hernia. The third patient developed a right ureteral stenosis with an intact bladder patch. The fourth child expired from maintained abdominal sepsis. The first 3 patients maintained normal graft function. There were no cases of thrombosis, arterial stenosis, or urinary leakages. These reported cases demonstrate that small pediatric en bloc transplantation of the multivisceral organs and dual kidneys with a bladder patch anastomosis is a feasible and less complex alternative to the standard procedure.

Combined off-pump coronary bypass grafting without heparin and liver transplantation: A novel approach to a complex dilemma.

Cardiac disease is a leading cause of early mortality for patients undergoing liver transplantation (LT), and severe coronary artery disease (CAD) is usually considered a contraindication for LT in patients with cirrhosis. Incidence of CAD in LT candidates has increased in recent years. While stable patients might be candidates for percutaneous interventions, patients with decompensated liver failure, or critical coronary lesions present a therapeutic challenge, and are often not considered candidates for LT. We present the case of a 60 year old male patient with decompensated liver failure, and critical CAD, who received successful combined off-pump coronary bypass grafting without heparin and LT using ex vivo normothermic liver perfusion machine. This approach represents a novel strategy to offer LT to this very selective group of patients.

Linezolid- and Vancomycin-resistant Enterococcus faecium in Solid Organ Transplant Recipients: Infection Control and Antimicrobial Stewardship Using Whole Genome Sequencing.

BACKGROUND: Vancomycin-resistant enterococci are an important cause of healthcare-associated infections and are inherently resistant to many commonly used antibiotics. Linezolid is the only drug currently approved by the US Food and Drug Administration to treat vancomycin-resistant enterococci; however, resistance to this antibiotic appears to be increasing. Although outbreaks of linezolid- and vancomycin-resistant Enterococcus faecium (LR-VRE) in solid organ transplant recipients remain uncommon, they represent a major challenge for infection control and hospital epidemiology. METHODS: We describe a cluster of 4 LR-VRE infections among a group of liver and multivisceral transplant recipients in a single intensive care unit. Failure of treatment with linezolid in 2 cases led to a review of standard clinical laboratory methods for susceptibility determination. Testing by alternative methods including whole genome sequencing (WGS) and a comprehensive outbreak investigation including sampling of staff members and surfaces was performed. RESULTS: Review of laboratory testing methods revealed a limitation in the VITEK 2 system with regard to reporting resistance to linezolid. Linezolid resistance in all cases was confirmed by E-test method. The use of WGS identified a resistant subpopulation with the G2376C mutation in the 23S ribosomal RNA. Sampling of staff members' dominant hands as well as sampling of surfaces in the unit identified no contaminated sources for transmission. CONCLUSIONS: This cluster of LR-VRE in transplant recipients highlights the possible shortcomings of standard microbiology laboratory methods and underscores the importance of WGS to identify resistance mechanisms that can inform patient care, as well as infection control and antibiotic stewardship measures.

Fibrinolysis Shutdown Is Associated With Thrombotic and Hemorrhagic Complications and Poorer Outcomes After Liver Transplantation.

Detrimental consequences of hypofibrinolysis, also known as fibrinolysis shutdown (FS), have recently arisen, and its significance in liver transplantation (LT) remains unknown. To fill this gap, this retrospective study included 166 adults who received transplants between 2016 and 2018 for whom baseline thromboelastography was available. On the basis of percent of clot lysis 30 minutes after maximal amplitude, patients were stratified into 3 fibrinolysis phenotypes: FS, physiologic fibrinolysis, and hyperfibrinolysis. FS occurred in 71.7% of recipients, followed by physiologic fibrinolysis in 19.9% and hyperfibrinolysis in 8.4%. Intraoperative and postoperative venous thrombosis events occurred exclusively in recipients with the FS phenotype. Intraoperative thrombosis occurred with an overall incidence of 4.8% and was associated with 25.0% in-hospital mortality. Incidence of postoperative venous thrombosis within the first month was deep venous thrombosis/pulmonary embolism (PE; 4.8%) and portal vein thrombosis/hepatic vein thrombosis (1.8%). Massive transfusion of ≥20 units packed red blood cells was required in 11.8% of recipients with FS compared with none in the other 2 phenotype groups (P = 0.01). Multivariate analysis identified 2 pretransplant risk factors for FS: platelet count and nonalcoholic steatohepatitis/cryptogenic cirrhosis. Recursive partitioning identified a critical platelet cutoff value of 50 × 109 /L to be associated with FS phenotype. The hyperfibrinolysis phenotype was associated with the lowest 1-year survival (85.7%), followed by FS (95.0%) and physiologic fibrinolysis (97.0%). Infection/multisystem organ failure was the predominant cause of death; in the FS group, 1 patient died of exsanguination, and 1 patient died of massive intraoperative PE. In conclusion, there is a strong association between FS and thrombohemorrhagic complications and poorer outcomes after LT.

Visceral arterial embolization prior to multivisceral transplantation in recipient with cirrhosis, extensive portomesenteric thrombosis, and hostile abdomen: Performance and outcome analysis.

Multivisceral transplant (MVT) for cirrhosis, and portomesenteric vein thrombosis (PVT), is fraught with life-threatening thrombo-hemorrhagic complications. Embolization of native viscera has been attempted in a handful of cases with mixed results. We carried out a comparative analysis of angiographic, intra-operative, and pathological findings in three recipients of MVT who were deemed exceptionally high hemorrhagic risk and therefore underwent preoperative visceral embolization. All recipients were male with cirrhosis, PVT, and a surgical history indicative of diffuse visceral adhesions; status post-liver transplantation (n = 2) and proctocolectomy (n = 1). The first patient had two Amplatzer II embolization plugs placed 2 cm from the origins of celiac and superior mesenteric (SMA) arteries. Distal migration of the celiac plug into gastroduodenal artery (GDA) and ensuing ischemia reperfusion injury, presumably contributed to severe disseminated intravascular coagulation (DIC) and intra-operative mortality. In the other two recipients, distal Gelfoam embolization of the SMA, GDA, and splenic arteries was performed, and although remarkable hemorrhage and coagulopathy occurred, embolization, undoubtedly, facilitated exenteration and improved outcomes. Pathologic examination in these cases confirmed ischemic necrosis of eviscerated bowel. In conclusion, liver-sparing, preoperative distal embolization of native viscera with Gelfoam is beneficial, but entails several pitfalls. It should currently be reserved for MVT recipients who otherwise are at unacceptably high risk.

Bloodstream infection caused by enteric organisms during the first 6 months after intestinal transplant.

BACKGROUND: Data on bloodstream infection (BSI) due to enteric organisms are scarce. METHODS: This retrospective study (1/2009-5/2017) was aimed to evaluate the incidence of BSI episodes due to enteric organisms during the first 6 months after intestinal transplant (ITx). Differences between the first (2009-2012) and second period (2013-2017) were evaluated as they differed from each other in the perioperative fungal prophylaxis and immunosuppressive regimen. RESULTS: Fifty-five adult patients were analyzed. Twenty-eight (51%) patients developed a total of 51 episodes of BSI. Mean time from transplant to BSI was 85.5 ± 58.8 days. The most common organisms were Klebsiella pneumoniae (33%), Enterococcus spp (31%), and Candida spp (18%). Twenty-three (45%) were multidrug resistant. The most common sources were gut translocation (35%), central line infection (20%), and intra-abdominal abscess (14%). Biopsy-proven rejection was associated with 16 (31%) of the BSI episodes. Patients during the first period were more likely to develop BSI (79% vs 41%, P = 0.03). There were more episodes of rejection associated with BSI in the first period (45% vs 14%, P = 0.03). The rate of reoperation into the abdominal cavity within 2 weeks after ITx was higher and the transplant hospital stay was longer among those who developed BSI (P = 0.04 for both). CONCLUSIONS: Half of our patients developed BSI (typically during the first 3 months). Gut translocation was the most common source of BSI. Patients with rejection and/or enteritis should be monitored closely for BSI.

Thrombotic and hemorrhagic complications during visceral transplantation: risk factors, and association with intraoperative disseminated intravascular coagulation-like thromboelastographic qualities: a single-center retrospective study.

This study describes the risk of thrombotic and hemorrhagic complications, both intraoperatively, and up to 1 month following visceral transplantation. Data from 48 adult visceral transplants performed between 2010 and 2017 were retrospectively studied [32 multivisceral (MVTx); 10 isolated intestine; six modified-MVTx]. Intraoperatively, intracardiac thrombosis (ICT)/pulmonary embolism (PE) occurred in 25%, 0% and 0% of MVTx, isolated intestine and modified MVTx, respectively, and was associated with 50% (4/8) mortality. Preoperative portal vein thrombosis (PVT) was a significant risk factor for ICT/PE (P = 0.0073). Thromboelastography resembling disseminated intravascular coagulation (DIC) (r time <4 mm combined with fibrinolysis or flat-line) was statistically associated with occurrence of ICT/PE (P < 0.0001). Compared to subgroup without ICT/PE, occurrence of ICT/PE was associated with an increased demand for all blood product components both overall, and each surgical stage. Hyperfibrinolysis (56%) was identified as cause of bleeding in MVTx. Incidence of postoperative thrombotic event at 1 month was 25%, 30% and 17% for MVTx, isolated intestine and modified MVTx, respectively. Incidence of postoperative bleeding complications at 1 month was 11%, 20% and 17% for MVTx, isolated intestine and modified MVTx. In conclusion, MVTx recipients with preoperative PVT are at an increased risk of developing intraoperative life-threatening ICT/PE events associated with DIC-like coagulopathy.

Comparison in outcome with tailored antibiotic prophylaxis postoperatively in pediatric intestinal transplant population.

BIs are ubiquitous among the pediatric intestinal transplant patient population. Personalizing postoperative prophylaxis antibiotic regimens may improve outcomes in this population. A retrospective analysis of all pediatric patients who underwent intestinal transplantation was evaluated to compare standardized and tailored regimens of antibiotics provided as prophylaxis postoperatively. Patients in the standard group have both shorter time to and higher rate of BIs, which was statistically significant (P < 0.001). Of the children who developed a BI, there was no statistical difference in average times to the development of a second BI (293 vs 119 days, P = 0.211). The tailored group had prolonged times until the development of a MDRO (52.6 vs 63.9 days, P = 0.677). Although not statistically significant, the tailored group had a propensity to present with gram-negative pathogens after transplant as compared to the standard regimen group, which presented with gram-positive pathogens (P = 0.103). Children with a history of an MDRO held a 7.3 (P < 0.01) times more likelihood of death within a year of transplant. A tailored prophylactic antibiotic regimen in the post-transplant period appears to prolong the time to the first BI. Although the data do not show differences in mortality, further study may prove the impact of a tailored antibiotic regimen on morbidity and mortality rates.

A nationwide analysis of re-exploration after liver transplant.

BACKGROUND: A retrospective review to investigate rate and outcomes of re-exploration following liver transplantation in the United States. METHODS: The NIS database was used to examine outcomes of patients who underwent re-exploration following liver transplantation from 2002 to 2012. Multivariate regression analysis was performed to compare outcomes of patients with and without reoperation. RESULTS: We sampled a total of 12,075 patients who underwent liver transplantation. Of these, 1505 (12.5%) had re-exploration during the same hospitalization. Hemorrhagic (67.9%) and biliary tract anastomosis complication (14.8%) were the most common reasons for reoperation. Patients with reoperation had a significantly higher mortality than those who did not (11.6% vs. 3.8%, AOR: 3.01, P < 0.01). Preoperative coagulopathy (AOR: 1.71, P < 0.01) and renal failure (AOR: 1.57, P < 0.01) were associated with hemorrhagic complications. Peripheral vascular disorders (AOR: 2.15, P < 0.01) and coagulopathy (AOR: 1.32, P < 0.01) were significantly associated with vascular complications. Risk of wound disruption was significantly higher in patients with chronic pulmonary disease (AOR: 1.50, P < 0.01). CONCLUSION: Re-exploration after liver transplantation is relatively common (12.5%), with hemorrhagic complication as the most common reason for reoperation. Preoperative coagulation disorders significantly increase hemorrhagic and vascular complications. Further clinical trails should investigate prophylactic strategies in high risk patients to prevent unplanned reoperation.

Clinical outcomes of intestinal transplant recipients colonized with multidrug-resistant organisms: a retrospective study.

Rates of multidrug-resistant organisms (MDRO) colonization among intestinal transplant (ITx) recipients have not been reported. Colonization rates with vancomycin-resistant Enterococcus (VRE), carbapenem-resistant Gram-negative bacteria (CR-GNB), and methicillin-resistant Staphylococcus aureus (MRSA) were obtained retrospectively in adults undergoing ITx (isolated or multivisceral) from 1/2009 to 12/2015. We assessed for VRE, CR-GNB, and MRSA bacteremia during the first year post-transplant for patients colonized with VRE, CR-GNB, and MRSA, respectively, and for those who were not colonized. We evaluated whether the number of hospitalization days and one year post-transplant survival were different in MDRO-colonized patients. Forty-five ITx recipients were identified. Twenty-eight (62%) were colonized with MDRO [VRE in 22 (50%) patients, MRSA in seven (16%), and CR-GNB in six (15%)]. VRE and CR-GNB-colonized patients were more likely to develop VRE and CR-GNB bacteremia, respectively, than noncolonized patients [8/22 (36%) vs. 1/23 (4%), and 4/6 (67%) vs. 2/39 (5%), P < 0.05 for both]. There was no difference in one-year survival between MDRO-colonized and noncolonized patients. However, survival was lower among MDRO-colonized patients who developed VRE, CR-GNB, or MRSA bacteremia (P < 0.001). MDRO colonization was common among our ITx recipients. VRE and CR-GNB bacteremia was more common among colonized patients, and survival was lower among MDRO-colonized patients who developed bacteremia.

Multivisceral transplantation for diffuse splanchnic venous thrombosis.

PURPOSE OF REVIEW: The development of diffuse splanchnic venous thrombosis continues to be a challenging undertaking for patients waiting for liver transplantation, requiring the utilization of highly complex surgical techniques. The aim of this article is to review the status of multivisceral transplantation (MVT) in the setting of diffuse portomesenteric thrombosis. RECENT FINDINGS: Even though many anatomical reconstructions of the venous system have been proposed to revascularize the transplanted liver, there are only few articles describing the use of these techniques. Here we describe a succinct review of these alternatives with emphasis on MVT. SUMMARY: MVT is a complex procedure; however, it is the only one capable of reestablishing the venous anatomy and physiology of the abdominal cavity, resolving completely the effects of portal hypertension and the baseline disease.

Successful Treatment of Carbapenemase-Producing Pandrug-Resistant Klebsiella pneumoniae Bacteremia.

New antibiotic options are urgently needed for the treatment of carbapenem-resistant Enterobacteriaceae infections. We report a 64-year-old female with prolonged hospitalization following an intestinal transplant who developed refractory bacteremia due to a serine carbapenemase-producing pandrug-resistant isolate of Klebsiella pneumoniae. After failing multiple antimicrobial regimens, the patient was successfully treated.

Clinical significance of intragraft miR-122 and -155 expression after liver transplantation.

AIM: Recurrent hepatitis C (RHC) and acute cellular rejection (AR) remain critical problems following liver transplantation (LT) in hepatitis C virus (HCV) positive recipients because of the similar clinical features. Discrimination between these conditions can be problematic, and adjunctive biomarkers would be useful to discriminate these processes. The aim of our study was to investigate the possibility of the intragraft miR-122 and -155 expression as new biomarkers after LT. METHODS: A total of 29 HCV positive recipients were enrolled in this study. Intragraft expressions of miR-122 and -155 were studied between RHC predominant (n = 17) and AR predominant cases (n = 12) using quantitative reverse transcription polymerase chain reaction. Furthermore, we investigated the correlations between these expression levels and clinical serum parameters. RESULTS: Intragraft miR-122 expression had a good correlation with serum alkaline phosphatase (P = 0.02), but it was not correlated with the serum HCV viral load. The expression levels of miR-122 in the AR group were significantly higher than those in the RHC group (P = 0.0006) and, inversely, the expression levels of miR-155 in the AR group were significantly lower than those in the RHC group (P = 0.01). CONCLUSION: Our study emphasizes a useful pattern of miR-122 and -155 as ancillary markers to discriminate AR predominant cases from RHC in HCV positive patients after LT.