A Case Report of Severe Hepatic Artery Vasospasm Induced by Hepatic Arterial Buffer Response After Liver Transplantation.

The management of severe hepatic artery vasospasm soon after liver transplantation (LT) is challenging because it can lead to hepatic artery thrombosis and subsequent graft failure. A 61-year-old man with hepatitis C cirrhosis and portal vein thrombosis received a deceased donor LT. On postoperative day 1, Doppler ultrasonography revealed a high-resistance waveform in the hepatic artery. Angiography showed severe vasospasm of the donor hepatic artery on postoperative day 3. Strong hepatic arterial buffer response (HABR) was considered for this etiology due to high portal vein velocity. Therefore, vasodilators, including nitroglycerin and prostaglandin E1, were initiated. The waveform of the hepatic artery vasospasm gradually improved as portal vein velocity decreased by Doppler ultrasonography within 7 days after LT. In conclusion, hepatic arterial buffer response can induce hepatic artery vasospasm immediately after LT. This vasospasm type may be managed conservatively with a positive outcome.

Extra-anatomical Meso-portal Venous Jump Graft Repair for Early Portal Vein Thrombosis After Liver Transplant in an Infant With a Hypoplastic Portal Vein: A Case Report.

BACKGROUND AND PURPOSE: Small infants with biliary atresia and hypoplastic portal veins (PV) are at risk for portal vein thrombosis (PVT) after liver transplantation (LT), which can lead to graft loss and mortality. Extra-anatomical PV reconstruction techniques have been established for adult cases of PVT; however, they have not been widely accepted for infants. METHODS: Here, we report the successful use of an extra-anatomical meso-portal venous jump graft to treat early PVT after LT in a 6-month-old infant with biliary atresia and PV hypoplasia. At the time of LT, despite a reduced-sized left lateral graft, we had to create a temporary abdominal closure with silastic mesh. FINDINGS: On postoperative day 1, PVT was detected by Doppler ultrasound of the liver. Surgical thrombectomy was attempted. We removed the blood clots and reconstructed the PV using an interposition venous graft. As the PV flow was still not sufficient, we performed an extra-anatomical meso-portal venous jump graft procedure from the recipient superior mesenteric vein to the donor PV. This resulted in a significant improvement in PV flow. CONCLUSION: For small infants at high risk for PVT, a detailed pretransplantation surgical plan and treatment options for possible early PVT are mandatory. An extra-anatomical meso-portal venous jump graft is a viable surgical technique for early PVT in infants.

Clinical management and humoral immune responses to rabies post-exposure prophylaxis among three patients who received solid organs from a donor with rabies.

BACKGROUND: The rabies virus causes a fatal encephalitis and can be transmitted through organ transplantation. In 2013, a man developed rabies 18 months after receiving a kidney from a donor with rabies, who was not known to have been infected when the organs were procured. Three additional persons who received organs from the same donor (liver, kidney, heart), all of whom were not vaccinated for rabies before transplantation, received rabies post-exposure prophylaxis (PEP) with rabies immune globulin and 5 doses of rabies vaccine as soon as the diagnosis of rabies was made in the donor (18 months after their transplant surgeries). We describe their clinical management. METHODS: As the 3 recipients were all on immunosuppressive medications, post-vaccination serologic testing was performed using the rapid fluorescent focus inhibition test to measure rabies virus neutralizing antibodies (RVNAs). An acceptable antibody response to administration of rabies vaccine was defined as detection of RVNAs at a concentration ≥0.1 IU/mL from a serum specimen collected ≥7 days after the fifth vaccine dose. RESULTS: All 3 recipients demonstrated an acceptable antibody response despite their immunosuppressed states. More than 36 months have passed since their transplant surgeries, and all 3 recipients have no evidence of rabies. CONCLUSIONS: The survival of 3 previously unvaccinated recipients of solid organs from a donor with rabies is unexpected. Although the precise factors that led to their survival remain unclear, our data suggest that PEP can possibly enhance transplant safety in settings in which donors are retrospectively diagnosed with rabies.

Eculizumab Salvage Therapy for Antibody-Mediated Rejection in a Desensitization-Resistant Intestinal Re-Transplant Patient.

The presence of elevated calculated panel reactive antibody (cPRA) and anti-HLA donor specific antibodies (DSA) are high risk factors for acute antibody-mediated rejection (AAMR) in intestinal transplantation that may lead to graft loss. Eculizumab has been used for the treatment of AAMR in kidney transplantation of sensitized patients that do not respond to other treatment. Here, we report a case where eculizumab was used to treat AAMR in a desensitization-resistant intestinal re-transplant patient. A male patient lost his intestinal graft to AAMR 8.14 years after his primary transplant. He received a second intestinal graft that had to be explanted a month later due to refractory AAMR. The patient remained highly sensitized despite multiple treatments. He received a multivisceral graft and presented with severe AAMR on day 3 posttransplantation. The AAMR was successfully treated with eculizumab. The patient presently maintains an elevated cPRA level above 90% but his DSAs have decreased from 18 000 MFI (mean fluorescent intensity) to below the positive cut-off value of 3000 MFI and remains rejection free with a 2-year follow-up since his multivisceral transplant. Eculizumab offers an alternative to treat AAMR in intestinal transplantation in desensitization-resistant patients.

A large-scale, rapid public health response to rabies in an organ recipient and the previously undiagnosed organ donor.

This article describes and contrasts the public health response to two human rabies cases: one organ recipient diagnosed within days of symptom onset and the transplant donor who was diagnosed 18 months post-symptom onset. In response to an organ-transplant-related rabies case diagnosed in 2013, organ donor and recipient investigations were conducted by multiple public health agencies. Persons with potential exposure to infectious patient materials were assessed for rabies virus exposure. An exposure investigation was conducted to determine the source of the organ donor's infection. Over 100 persons from more than 20 agencies spent over 2700 h conducting contact investigations in healthcare, military and community settings. The 564 persons assessed include 417 healthcare workers [5.8% recommended for post-exposure prophylaxis (PEP)], 96 community contacts (15.6% recommended for PEP), 30 autopsy personnel (50% recommended for PEP), and 21 other persons (4.8% recommended for PEP). Donor contacts represented 188 assessed with 20.2% recommended for PEP, compared with 5.6% of 306 recipient contacts recommended for PEP. Human rabies cases result in substantial use of public health and medical resources, especially when diagnosis is delayed. Although rare, clinicians should consider rabies in cases of encephalitis of unexplained aetiology, particularly for cases that may result in organ donation.

Use of the recipient celiac trunk for hepatic artery reconstruction in orthotopic liver transplantation.

Arterial complications contribute to significant morbidity and mortality after liver transplantation (OLT). If hepatic artery inflow to the graft is inadequate, alternative approaches can be considered, such as supraceliac or infrarenal aortic conduits and splenic artery as an arterial inflow. Between January 2005 and January 2012, we performed 928 OLTs. We used the recipient celiac trunk for arterial inflow in 9 patients (1%). evaluated retrospectively, We the indications, results, and outcome of this technique. Doppler ultrasound of the liver was used to evaluate arterial flow. Eight cases are first transplant and 1 case is a second transplant. Five cases are pediatric recipients and four cases are adult recipients. Male to female ratio is 3/6. Average follow-up is 23 months. No complications were encountered as a result of sacrificing the branches of the celiac axis. The conclusion is that the celiac trunk provides an adequate arterial inflow in OLT when the recipient's hepatic artery is not suitable to use.

Factor V Leiden mutation is a risk factor for hepatic artery thrombosis in liver transplantation.

BACKGROUND: Hepatic artery thrombosis (HAT) after orthotopic liver transplantation (OLT) is associated with significant morbidity and mortality. Factor V Leiden (FVL) mutation is the most common genetic defect that predisposes to thrombosis. The reconstruction of hepatic artery with arterial graft is a documented risk factor for HAT. However, the relationship among FVL mutation, arterial graft, and HAT remains to be determined. METHODS: We randomly genotyped 485 patients who underwent OLT from April 2002 to January 2011 and studied the incidence of Hepatic artery thrombosis in the presence of FVL mutation. RESULTS: Of 485 patients, 21 patients (4.3%) developed HAT (13 male, 8 female); 10 patients (4 male, 6 female) were heterozygous for the FVL mutation. The incidences of HAT in patients without versus with the FVL mutation were 3.8% and 30% (P = .007). Of patients with HAT, 8 hepatic arteries were reconstructed with infrarenal aortic conduits. All 3 patients (100%) with vs 5 (28%) without FVL who received arterial grafts developed HAT (P = .042). CONCLUSION: Our study suggested that the FVL mutation may be a risk factor for HAT in liver transplantation; the risk is augmented in the presence of an arterial graft.

Comparative analysis of T-cell depletion method for clinical immunotherapy-anti-hepatitis c effects of natural killer cells via interferon-γ production.

Liver transplantation (LT) is a life-saving treatment for liver cirrhosis patients with hepatocellular carcinoma (HCC). However, 10%-20% HCC recurrence rate after LT is due to the immunosuppression inducing tumor growth. We recently reported a novel immunotherapy with donor liver natural killer (NK) cells to prevent HCC and hepatitis C virus (HCV) recurrence after LT. In this cell processing procedure, Muromonab-CD3 (Orthoclone OKT3, an anti-CD3 antibody) was added to the culture medium to deplete CD3(+) T cells to prevent graft-versus-host disease. However, the manufacture of OKT3 was discontinued in 2010, when other treatments with similar efficacy and fewer side effects became available. In this study, we examined alternative reagents for T-cell depletion-MACS GMP CD3 pure (GMP CD3), antithymocyte globulin, and alemtuzumab-for NK cell immunotherapy in the allogeneic setting. We observed that GMP CD3 showed exactly the same effects on liver mononuclear cells as OKT3, including activation of NK cells and depletion of T cells. Interestingly, binding of T-cell depletion antibodies to NK cells led to an anti-HCV effect via interferon-γ production. These results with the use of in vitro culture systems suggested that antibodies which produce T-cell depletion affected NK cell function.

Citrulline level is a potent indicator of acute rejection in the long term following pediatric intestinal/multivisceral transplantation.

Citrulline has been advocated as a marker for acute cellular rejection (ACR) in intestinal transplantation; however, its significance as a forewarning in the long-term follow-up remains unknown. This study aimed to investigate the association between citrulline levels and the grading of ACR to establish a cutoff point that accurately predicts ACR beyond 3 months posttransplant in the pediatric patient population. During a 16-year period (1995-2011), a total of 13 499 citrulline samples were prospectively collected from 111 consecutive pediatric intestinal/multivisceral transplant recipients: 2155 were obtained concurrently with intestinal biopsies. There were 185 ACR episodes observed among 74/111 (67%) patients (median follow-up: 4.4 years). Citrulline levels were inversely proportional to the severity of ACR. Negative predictive values for any type of ACR (cutoff, 20 µmol/L) and moderate/severe ACR (cutoff, 10 µmol/L) were 95% and 99%, respectively. When patients were divided according to graft size, diagnostic accuracy using the same cutoff was identical. Similarly, subgroup analysis by the timing of citrulline measurement prior to biopsy varying from 1 to 7 days demonstrated comparable results. Citrulline is a potent indicator as a danger signal for ACR, being an exclusionary, noninvasive biomarker with excellent negative predictive values in the long term after pediatric intestinal/multivisceral transplant.

Predisposing factors of diminished survival in simultaneous liver/kidney transplantation.

Since the adoption of the Model for End-Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death-censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow-up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1-7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1-7.2) and female donor gender (HR 2.9, 95% CI 1.1-7.9). For death-censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5-27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death-censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6-21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long-term outcomes.

MicroRNA signature of intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies.

Despite continuous improvement of immunosuppression, small bowel transplantation (SBT) is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need to uncover novel insights that will lead to strategies to achieve better control of ACR. We hypothesized that particular miRNAs provide critical regulation of the intragraft immune response. The aim of our study was to identify miRNAs involved in intestinal ACR. We examined 26 small intestinal mucosal biopsies (AR/NR group; 15/11) obtained from recipients after SBT or multivisceral transplantation. We investigated the expression of 384 mature human miRNAs and 280 mRNAs associated with immune, inflammation and apoptosis processes. We identified differentially expressed 28 miRNAs and 58 mRNAs that characterized intestinal ACR. We found a strong positive correlation between the intragraft expression levels of three miRNAs (miR-142-3p, miR-886-3p and miR-132) and 17 mRNAs including CTLA4 and GZMB. We visualized these miRNAs within cells expressing CD3 and CD14 proteins in explanted intestinal allografts with severe ACR. Our data suggested that miRNAs have a critical role in the activation of infiltrating cells during intestinal ACR. These differences in miRNA expression patterns can be used to identify novel biomarkers and therapeutic targets for immunosuppressive agents.

Split liver transplantation.

We analyzed the results of 55 patients who underwent split liver transplantation at our center between September 1996 and December 2008, 30 adults (54.5%) and 25 children (45.5%). Median follow-up was 12 years. Overall patient survival was 71%, adult 70% and pediatric 72%. Mean patient survival was 61.58 months, and mean graft survival was 44.35 months. Pediatric survival and pediatric graft survival after 1 and 5 years were 84% and 72% and 72% and 52.4%, respectively. Adult survival and adult graft survival after 1 and 5 years were 75% and 66.2% and 60.7% and 51.5%, respectively. Twelve patients required retransplantation, 6 for primary nonfunction, 3 for chronic rejection, and 3 for vascular complications. Blood groups of the recipient patients were: 34 O, 14 A, 7 B, and 0 AB. The use of split liver for adult and pediatric populations allows us to expand the cadaveric donor pool and has the potential to significantly reduce waiting list mortality, especially for certain blood groups.

Association between panel reactive antibodies and acute small bowel rejection: analysis of a series of 324 intestinal transplants.

INTRODUCTION: Panel reactive antibodies (PRA) to class I and II HLA molecules have been associated with acute kidney graft rejection, but their role in small bowel transplantation has not been characterized. METHODS: Since 1994, 324 SBT, alone or as multivisceral transplantation (MVT), have been performed in 286 patients. Routine and surveillance biopsies were performed to rule out or confirm acute rejection (AR), and PRA quantification was performed at varying intervals. We obtained data from 110 patients and 651 PRA measurements. While AR grade (mild to severe, grades 1-3) was determined by histopathological analysis, the status of no AR was determined also by clinical data. When biopsy samples or PRA measurements were frequent around an AR episode within periods of 7 days, the highest value was used. RESULTS: A comparison could be made between 259 instances in which there was a PRA measurement and simultaneous rejection evaluation. Positive PRA showed association with AR (P < 0.001). The positive and negative predictive values were 44% and 79%, respectively. No correlation was found in the severity of rejection. CONCLUSION: The presence of increased levels of PRA is a risk factor of rejection in small bowel transplantation. Alloantibody-mediated injury to the graft contributes frequently to acute rejection of small bowel, and it is associated with cell-mediated immunity in variable proportion.

Combined pancreas and en bloc kidney transplantation using a bladder patch technique from very small pediatric donors.

Very small pediatric donors are underutilized for pancreas and kidney transplantation for the fear of inadequate islet mass and higher incidence of technical complications, and the lower age limit for such donors is not well defined. We present here two cases of combined pancreas and en bloc kidney transplantation from very small pediatric donors (14 and 18 months old) to adult type 1 diabetic and uremic patients. The conventional surgical procedure for simultaneous pancreas and kidney transplantation with systemic venous and bladder exocrine drainage was successfully applied to very small organs. For both, we utilized the recently described bladder patch technique for ureteral reconstruction. One patient developed venous thrombosis (partial thrombosis of the splenic and mesenteric veins) and the other urine leak (from a midportion of the medial ureter without compromising the bladder patch) after the transplants; both were successfully managed and the patients demonstrated immediate and sustained pancreas and kidney graft functions for 12 and 2 months posttransplantation. These cases illustrate the feasibility of combined pancreas and en bloc kidney transplantation from very small pediatric donors using a bladder patch technique to avoid small ureteral anastomosis.

Citrulline evaluation in bowel transplantation.

INTRODUCTION: The purpose of this study was to evaluate the correlation of plasma citrulline and rejection episodes in intestinal transplantation. METHODS: From January 2007 until present, we performed citrulline assays on our small bowel patients. We investigated the correlation of these assays with the rejection status of the patients. The rejection status of the graft was defined based on graft biopsies. RESULTS: Of 5195 citrulline samples, average serum citrulline levels decreased significantly when the patients presented a rejection episode. We found the following: no rejection, 17.38 microm/L; mild rejection, 13.05 microm/L; moderate rejection, 7.98 microm/L; and severe rejection, 6.05 microm/L. Our current emphasis is to determine the predictive power of citrulline with other biomarkers versus as a separate and isolated measurement. CONCLUSIONS: In our study, citrulline levels correlated significantly with the rejection status of the graft. Serial follow-up of the patients using this assay may alert us to the possibility of increased alloreactivity and rejection episodes.

International grading scheme for acute cellular rejection in small-bowel transplantation: single-center experience.

A standardized grading scheme for the assessment of acute cellular rejection (ACR) in small-intestine transplantation was proposed in 2003 at the Eighth International Small Intestinal Transplantation Symposium. We have implemented the current grading scheme for ACR in small-bowel transplantation since October 2003. The pathologic diagnoses of those small-intestine biopsy samples, including ACR grade and other supplementary findings were evaluated. A total of 3484 small intestine biopsy samples from 155 patients were available for evaluation in this study. Frequency of grades 0, indeterminate, 1, 2, and 3 acute cellular rejection was 33.9%, 49.1%, 12.6%, 3.7%, and 0.8%, respectively. Duration of ACR episode strongly correlated with grade of ACR episode (P < .001). Other supplementary findings included acute vascular rejection component, 2.2%; increase in lymphoplasmacytic infiltrate in lamina propria, 15.7%; mucosal fibrosis, 0.4%; and regenerative changes, 0.3%. Our data substantiate that this grading system is reliable and useful for clinical decision making in bowel transplantation. We suggest that an assessment and quantification of supplementary findings be considered a component of the International Pathology Grading Scheme.

Immediate antibody-mediated (hyperacute) rejection in small-bowel transplantation and relationship to cross-match status and donor-specific C4d-binding antibodies: case report.

BACKGROUND: The role of preformed donor-specific antibodies (DSAs) as a barrier to isolated intestinal transplantation (ITx) remains ambiguous; thus, a positive cross-match has not been a contraindication to ITx. OBJECTIVE: To report the case of a patient with Crohn's disease who underwent ITx and developed immediate antibody-mediated rejection on reperfusion of the allograft. METHODS: Percent reactive antibody testing was performed using pretransplantation serum samples and at transplantation using bead-based assays (Luminex, Luminex Corp, Austin, Tex) and flow cytometry solid-phase assays (FlowPRA single-antigen beads (One Lambda, Inc, Canoga Park, Calif). Serologic tests, flow cytometry cross-matching, and flow cytometry assays of C4d-binding serum antibodies were also performed. Histologic and immunofluorescent analysis of biopsy specimens was performed. RESULTS: HLA typing revealed no sharing of class I or II antigens between donor and recipient. Pretransplantation donor-specific antibodies (DSA) were present at transplantation. Cross-matching (performed during surgery) was positive for class I and II by serologic testing and flow cytometry. After reperfusion, the graft immediately developed severe ischemic injury and arteritis on mucosal biopsy specimens, with immunoglobulin deposition. The DSA C4d binding antibodies were also present. After intense immunosuppression and plasmapheresis, the graft and the biopsy histologic findings showed marked improvement (day 2). By day 7 posttransplantation, patient and graft status were stable. The patient has remained clinically stable for more than a year after transplantation. CONCLUSIONS: Pretransplant DSA in ITx can be a risk factor for immediate (hyperacute) but potentially reversible antibody-mediated rejection. Thus, pretransplantation DSA and cross-match results are critical components to be considered in patients awaiting or undergoing ITx.

Abdominal wall transplantation: surgical and immunologic aspects.

Abdominal wall transplantation is a type of composite tissue allograft that can be utilized to reconstitute the abdominal domain of patients undergoing intestinal transplantation. We have presented herein combined experience and long-term follow-up results of a series of abdominal wall transplants performed at 2 institutions. A total of 15 abdominal wall transplants from cadaveric donors were performed in 14 patients at the end of intestinal transplant surgery or, in 2 cases, a few days after the primary intestinal transplant. The vascular supply was through the inferior epigastric vessels, from the iliac vessels in 12 cases and via a microsurgical technique in 3 cases. Immunosuppression consisted of induction with alemtuzumab and maintenance treatment with tacrolimus monotherapy. Two grafts lost to vascular thrombosis were removed. Five patients are still alive, although all deaths were unrelated to the abdominal wall transplant. There were 3 episodes of abdominal wall graft rejection, treated with steroids; the abdominal wall graft and the intestinal grafts experienced rejection independent from each other. In summary, abdominal wall transplantation is a feasible technique for recipients of intestinal or multivisceral transplants, when the closure of the abdominal cavity by primary intention is technically impossible.

Surgical considerations in liver transplantation: small for size syndrome.

The chronic shortage of cadaveric grafts for patients on the liver transplant list has resulted in wide implementation of living donor liver transplant (LDLT) and split cadaveric liver transplantation (SLT). Small for size syndrome (SFSS) is a significant complication that can occur during LDLT or SLT. It is generally defined as the presence of prolonged cholestasis, coagulopathy and ascites within the first week from transplant. Multiple factors contribute to the pathogenesis of SFSS, such as overall graft size, portal hyperperfusion, impaired venous outflow, as well as donor and recipient factors. Strategies utilized to minimize or resolve SFSS include the use of right lobe grafts, modulation of portal flow by splenic artery ligation, splenectomy or porto-systemic bypass, and optimization of venous outflow. Additional surgical techniques to avoid SFSS include the use of auxiliary orthotopic liver grafts and dual liver graft transplantation. Careful consideration of risk to the LDLT donor has to be taken whenever right lobe graft is utilized, especially if the middle hepatic vein (MVH) is going to be included in the graft.