Antithymocyte Globulin Use for Corticosteroid Nonresponsive Rejection After Liver Transplantation.

BACKGROUND AND AIMS: Acute cellular rejection after liver transplantation usually responds to intravenous corticosteroids, yet some episodes are corticosteroid-nonresponsive. We report our experience using antithymocyte globulin therapy for corticosteroid-nonresponsive acute cellular rejection in liver transplant recipients. METHODS: From January 1, 2002 to January 1, 2010, 1436 patients underwent 1548 liver or liver with other organ transplantations at our institution. We identified all patients treated with antithymocyte globulin during this timeframe for corticosteroid-nonresponsive rejection. RESULTS: Twenty patients required antithymocyte globulin for 21 episodes of corticosteroid-nonresponsive rejection. Antithymocyte globulin was started a median (range) of 27 (7-2434) days post-transplantation, and median total antithymocyte globulin dose and duration was 10.5 (7.5-26.25) mg/kg and 7 (5-13) days, respectively. Resolution or marked histological improvement of rejection on Day 7 liver allograft biopsies occurred in 90% of rejection episodes treated with antithymocyte globulin. Three-year graft and patient survival rates were 60% and 65%, respectively, compared with 79% and 84% in patients not requiring antithymocyte globulin. CONCLUSIONS: Antithymocyte globulin was an effective therapy for corticosteroid-nonresponsive rejection, with excellent short-term outcomes. Some liver transplant recipients failed to respond, and long-term survival was reduced, even in those who responded to antithymocyte globulin.

Clinical outcomes of hepatitis C treatment before and after kidney transplantation and its impact on time to transplant: A multicenter study.

Waitlist time for kidney transplantation is long but may be shortened with the utilization of hepatitis C positive allografts. We retrospectively reviewed the course of 36 hepatitis C positive patients awaiting kidney transplantation at 2 large centers within the same health system, with near-identical care delivery models with the exception of timing of hepatitis C treatment, to determine the impact of timing of hepatitis C treatment on access to transplant, waitlist time, and treatment efficacy and tolerability. The majority of patients had hepatitis C genotype 1a or 1b, and all received direct acting antiviral therapy with 100% treatment response. One patient underwent transplantation in the pretransplant treatment group. The 1-year transplantation rate was 12.5% vs 67.9% (P = .0013) in those treated posttransplantation. The median waitlist time in the posttransplant group was 122 (interquartile range [IQR] 21.5, 531.0) days, which was significantly shorter than the center's regional and national wait time. Pathologic review revealed no difference in allograft quality. Overall treatment related adverse events were not different between the 2 groups. A strategy of posttransplant hepatitis C treatment increased access to transplant and reduced waitlist time. Delaying treatment until after transplant did not appear to adversely affect recipients' kidney allograft or overall survival.

Thromboelastography as a Predictor of Outcomes Following Liver Transplantation.

BACKGROUND: Thromboelastography (TEG) has been used perioperatively during liver transplantation (LT) to provide a real-time global hemostasis assessment for targeted blood product replacement. We aimed to analyze the relationship between post-LT TEG results and outcomes. METHODS: We retrospectively analyzed patients undergoing LT from November 2008 to December 2014 at Mayo Clinic Florida. All 441 single-organ 1st-time LT patients aged ≥18 years requiring post-LT intensive care unit management were included. TEG parameters including r time, k time, α angle, and maximum amplitude were measured regularly during the first 24 hours after LT. Outcomes included return to the operating room secondary to bleeding, length of hospitalization, survival, and early allograft dysfunction. RESULTS: A prolonged and/or lengthening r time, k time, and r+k time were all independently associated with increased length of hospitalization after LT. Increased maximum amplitude on the first post-LT TEG was associated with early allograft dysfunction. No notable associations of TEG parameters with survival or return to operating room were observed. CONCLUSIONS: The association of absolute and temporal TEG value changes with increased length of hospitalization and early allograft dysfunction suggests that TEG may have a role in identifying patients at high risk for these outcomes.

Waitlist Outcomes for Patients Relisted Following Failed Donation After Cardiac Death Liver Transplant: Implications for Awarding Model for End-Stage Liver Disease Exception Scores.

Understanding of outcomes for patients relisted for ischemic cholangiopathy following a donation after cardiac death (DCD) liver transplant (LT) will help standardization of a Model for End-Stage Liver Disease exception scheme for retransplantation. Early relisting (E-RL) for DCD graft failure caused by primary nonfunction (PNF) or hepatic artery thrombosis (HAT) was defined as relisting ≤14 days after DCD LT, and late relisting (L-RL) due to biliary complications was defined as relisting 14 days to 3 years after DCD LT. Of 3908 DCD LTs performed nationally between 2002 and 2016, 540 (13.8%) patients were relisted within 3 years of transplant (168 [4.3%] in the E-RL group, 372 [9.5%] in the L-RL group). The E-RL and L-RL groups had waitlist mortality rates of 15.4% and 10.5%, respectively, at 3 mo and 16.1% and 14.3%, respectively, at 1 year. Waitlist mortality in the L-RL group was higher than mortality and delisted rates for patients with exception points for both hepatocellular carcinoma (HCC) and hepatopulmonary syndrome (HPS) at 3- to 12-mo time points (p < 0.001). Waitlist outcomes differed in patients with early DCD graft failure caused by PNF or HAT compared with those with late DCD graft failure attributed to biliary complications. In L-RL, higher rates of waitlist mortality were noted compared with patients listed with exception points for HCC or HPS.

Noneligible Donors as a Strategy to Decrease the Organ Shortage.

Organ procurement organization (OPO) performance is generally evaluated by the number of organ procurement procedures divided by the number of eligible deaths (donation after brain death [DBD] donors aged <70 years), whereas the number of noneligible deaths (including donation after cardiac death donors and DBD donors aged >70 years) is not tracked. The present study aimed to investigate the variability in the proportion of noneligible liver donors by the 58 donor service areas (DSAs). Patients undergoing liver transplant (LT) between 2011 and 2015 were obtained from the United Network for Organ Sharing Standard Transplant Analysis and Research file. LTs from noneligible and eligible donors were compared. The proportion of noneligible liver donors by DSA varied significantly, ranging from 0% to 19.6% of total liver grafts used. In transplant programs, the proportion of noneligible liver donors used ranged from 0% to 35.3%. On linear regression there was no correlation between match Model for End-Stage Liver Disease score for programs in a given DSA and proportion of noneligible donors used from the corresponding DSA (p = 0.14). Noneligible donors remain an underutilized resource in many OPOs. Policy changes to begin tracking noneligible donors and learning from OPOs that have high noneligible donor usage are potential strategies to increase awareness and pursuit of these organs.

Early Allograft Dysfunction After Liver Transplantation Is Associated With Short- and Long-Term Kidney Function Impairment.

Early allograft dysfunction (EAD) after liver transplantation (LT) is related to ischemia-reperfusion injury and may lead to a systemic inflammatory response and extrahepatic organ dysfunction. We evaluated the effect of EAD on new-onset acute kidney injury (AKI) requiring renal replacement therapy within the first month and end-stage renal disease (ESRD) within the first year post-LT in 1325 primary LT recipients. EAD developed in 358 (27%) of recipients. Seventy-one (5.6%) recipients developed AKI and 38 (2.9%) developed ESRD. Compared with those without EAD, recipients with EAD had a higher risk of AKI and ESRD (4% vs. 9% and 2% vs. 6%, respectively, p < 0.001 for both). Multivariate logistic regression analysis showed an independent relationship between EAD and AKI as well as ESRD (odds ratio 3.5, 95% confidence interval 1.9-6.4, and odds ratio 3.1, 95% confidence interval 11.9-91.2, respectively). Patients who experienced both EAD and AKI had inferior 1-, 3-, 5-, and 10-year patient and graft survival compared with those with either EAD or AKI alone, while those who had neither AKI nor EAD had the best outcomes (p < 0.001). Post-LT EAD is a risk factor for both AKI and ESRD and should be considered a target for future intervention to reduce post-LT short- and long-term renal dysfunction.

The Use of Donation After Cardiac Death Allografts Does Not Increase Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) recurrence in patients undergoing liver transplantation (LT) with donation after brain death (DBD) and donation after cardiac death (DCD) allografts has not previously been investigated. Rates and patterns of HCC recurrences were investigated in patients undergoing DBD (N = 1633) and DCD (N = 243) LT between 2003 and 2012. LT for HCC was identified in 397 patients (340 DBD and 57 DCD). No difference in tumor number (p = 0.26), tumor volume (p = 0.34) and serum alphafetoprotein (AFP) (p = 0.47) was seen between the groups. HCC recurrence was identified in 41 (12.1%) patients in the DBD group and 7 (12.3%) patients in the DCD group. There was no difference in recurrence-free survival (p = 0.29) or cumulative incidence of HCC recurrence (p = 0.91) between the groups. Liver allograft was the first site of recurrence in 22 (65%) patients in the DBD group and two (37%) patients in the DCD group (p = 0.39). LT for HCC with DBD and DCD allografts demonstrate no difference in the rate of HCC recurrence. Previously published differences in survival demonstrated between recipients with HCC receiving DBD and DCD allografts despite statistical adjustment can likely be explained by practice patterns not captured by variables contained in the SRTR database.

Avoiding stay in the intensive care unit after liver transplantation: a score to assign location of care.

Select liver transplantation (LT) recipients in our program are transferred from operating room to postanesthesia care unit for recovery and extubation with transfer to the ward, completely eliminating an intensive care unit (ICU) stay. Developing a reliable method to determine patients suitable for fast-tracking would be of practical benefit to centers considering this practice. The aim of this study was to create a fast-tracking probability score that could be used to predict successful assignment of care location after LT. Recipient, donor and operative characteristics were assessed for independent association with successful fast-tracking to create a probability score. Of the 1296 LT recipients who met inclusion criteria, 704 (54.3%) were successfully fast-tracked and 592 (45.7%) were directly admitted to the ICU after LT. Based on nine readily available variables at the time of LT, we created a scoring system that classified patients according to the likelihood of being successfully fast-tracked to the surgical ward, with an area under the curve (AUC) of 0.790 (95% CI: 0.765-0.816). This score was validated in an independent group of 372 LT with similar AUC. We describe a score that can be used to predict successful fast-tracking immediately after LT using readily available clinical variables.

Liver transplantation in patients with atrial fibrillation.

In this study we described survival and incidence of perioperative and postoperative complications in liver transplant recipients with known atrial fibrillation. A total number of 717 patients underwent liver transplantation between January 2005 and December 2008 at our institution. In this population, preoperative paroxysmal or chronic-persistent atrial fibrillation was diagnosed in 32 patients (4.5%). Of these, 12 patients died during follow-up and 4 patients required liver retransplantation. Perioperative cardiac complications occurred in 10 patients (31%) resulting in 3 cardiac-related deaths. Median patient survival was 1613 days (range, 22-2492) and median graft survival was 1524 days (range, 10-2492). Twenty patients are still alive with a median survival of 1861 days (range, 1189-2492) after liver transplantation.

Antithymocyte globulin induction and rapid steroid taper leads to excellent results in kidney transplantation with donation after cardiac death donors: importance of rejection and delayed graft function.

Recipients of primary transplants from donation after cardiac death (DCD) donors (n = 40) performed from January 2005 to December 2009 were retrospectively reviewed and compared with recipients of primary transplants from donation after brain death (DBD) donors (n = 142). Patients received rabbit antithymocyte globulin induction and rapid steroid taper (RST; steroids stopped 5 days after surgery). Maintenance immunosuppression included tacrolimus and mycophenolate mofetil. Protocol kidney biopsies, creatinine (Cr), and measured glomerular filtration rate (mGFR; determined by cold iothalamate or 24-h creatinine clearance) were obtained at 1, 4, 12, and 24 months. Kidney biopsies for cause were conducted for unexplained elevated Cr, decline in mGFR, or new proteinuria. Biopsies were graded for rejection according to the Banff criteria. Graft survival at 3 years was 90.0% for DCD recipients and 86.6% for DBD recipients (P = NS). Rejection of any grade diagnosed on any biopsy through the first 2 years occurred in 18 DCD (45%) and 50 DBD (35%) recipients. Rejection of a grade more than Banff borderline occurred in 12.5% DCD and 12.7% DBD recipients. At 2 years, the mean ± SEM Cr and mGFR for DCD recipients with rejection were 1.8 ± 0.29 mg/dL and 59.2 ± 8.5 mL/min versus 1.3 ± 0.11 mg/dL and 67.0 ± 7.8 ml/min for those without rejection. For DBD recipients with rejection, Cr and mGFR at 2 years were 1.7 ± 0.12 mg/dL and 54.0 ± 4.4 mL/min versus 1.4 ± 0.11 mg/dL and 66.6 ± 3.3 ml/min for those without rejection (P = NS). Comparing DCD to DBD, there was no statistical difference in mean Cr or mGFR outcomes. Regardless of group, grafts with delayed graft function had lower 3-year survival. DCD primary kidney transplant recipients treated with rabbit antithymocyte induction and RST have short-term graft survival and function equivalent to DBD recipients. RST appears to be acceptable immunosuppression for DCD recipients.

Association of surgeon with surgical site infection after liver transplantation.

Surgical site infection (SSI) after liver transplantation has been associated with increased risk of allograft loss and death. Identification of modifiable risk factors for these infections is imperative. To our knowledge, intraoperative practices associated with transplant surgeons have not been assessed as a risk factor. A retrospective cohort study of risk factors for SSI after 1036 first liver transplantations completed by seven surgeons at a single center between 2003 and 2008 was undertaken. Cox proportional hazards models were used to evaluate the association between surgeons and SSIs. SSIs were identified in 166 of 1036 patients (16%). Single variable analysis showed strong evidence of an association between surgeon and SSI (p = 0.0007); the estimated cumulative incidence of SSI ranged from 7% to 24%. This result was consistent in multivariable analysis adjusting for potentially confounding variables (p = 0.002). The occurrence of organ-space or deep SSI varied significantly among surgeons in both single variable analysis (p = 0.005) and multivariable analysis (p = 0.006). These findings provide evidence that differences in the surgical practices of individual surgeons are associated with risk for SSI after liver transplantation. Identification of specific surgical practices associated with risk of SSI is warranted.

Liver retransplantation in superobese patients: a single center experience.

A retrospective review of patients who had body mass indeces greater than 40 kg/m(2) who underwent liver retransplantation (LR) from February 1998 to December 2008 at our institution. There were 73 patients who had body mass indeces greater than 40 kg/m(2) and had orthotopic liver transplantation. Six of 73 patients required retransplantation. Median time between orthotopic liver transplantation and LR was 131 days (range, 2 to 2812 days). Indications for LR were ischemic cholangiopathy, hepatic necrosis, recurrent hepatitis C, and primary non-function. Four patients are still alive with median survival of 37 months after LR. Two patients had perioperative death.

Dual left lobe living donor liver transplantation using donors unacceptable for right lobe donation: a case report.

Living donor liver transplantation (LDLT) has become a viable alternative for end-stage liver disease. The shortage of brain-dead donors has led to development of advanced surgical approaches. Dual lobe LDLT has been performed successfully in the recent years. The major indication for this complex procedure has been insufficient graft size from a single donor or insufficient remnant in the donor. We performed a dual left lobe LDLT using 2 donors who were unacceptable for right lobe donation.

Primary nonfunction in liver transplantation: a single-center experience.

Primary nonfunction (PNF) after liver transplantation is life threatening. In recent review of data from Scientific Registry of Transplant Recipients on liver transplantations between 2002 and 2004, the rate of PNF was 5.8%. In this study, our aim was to review the incidence and outcome of PNF at our transplant center. From February 1998 through December 2007, 1679 liver transplants were performed. There were 24 PNF (1.4%) in 22 patients. The 6- and 12-month patient survival rates were 72.2% and 63.3%, respectively. Our results demonstrate a low incidence of PNF at our center. However, the patient survival outcome remains poor. Future investigations to improve survival among liver transplant recipients with PNF are essential.

Mesocaval shunt as an alternative treatment for persistent ascites after liver transplantation: case reports.

Refractory ascites after liver transplantation is a relatively rare complication. If the initial medical treatment fails, more invasive techniques may be required. The TIPS procedure has emerged as a major treatment option for decompression of the portal venous system. Mesocaval shunt can be an alternative to TIPS in selected cases. We describe two patients who underwent mesocaval shunt construction for refractory ascites.

Postoperative hematoma following inguinal herniorrhaphy: patient characteristics leading to increased risk.

BACKGROUND: Although relatively infrequent, groin hematoma following inguinal herniorrhaphy is a morbid complication with major ramifications of mesh infection and hernia recurrence. We have sensed an increasing frequency of this complication in our tertiary referral practice and sought to determine whether or not significant risk factors could be identified. METHODS: In this matched case-control study (1995-2003), we identified 53 patients with groin hematomas and paired them with 106 age- and gender-matched controls. Patient and procedure characteristics were analyzed using chi-square and both univariate and multivariable, conditional logistic regression analysis. RESULTS: The 53 patients developing groin hematoma following inguinal hernia repair (mean age=65, range 22-87, 90% male) were well matched with 106 controls (mean age=65, range 22-87, 90% male). There was no significant difference in the location (left, right, bilateral), type (direct, indirect, pantaloon, first repair, or recurrent), or technique of hernia repair (Bassini, Lichtenstein, mesh plug, endoscopic, or McVay) between groups. While univariate analysis identified Coumadin usage (P<0.001, hazard ratio 19.1), valvular disease (P<0.001, hazard ratio 10.9), atrial fibrillation (P=0.02, hazard ratio 4.2), vascular disease (P=0.04, hazard ratio 2.2), blood abnormalities (P=0.02, hazard ratio 3.2), and previous bleeding episodes (P=0.02, hazard ratio 4.9) as significant factors, only preoperative Coumadin usage was important in multivariate analysis. CONCLUSION: The crucial risk factor for groin hematoma developing in patients undergoing inguinal hernia repair is preoperative need for Coumadin therapy. Although the perioperative management of anticoagulation in patients undergoing inguinal herniorrhaphy is not clearly defined, meticulous management of patients requiring Coumadin therapy seems prudent.

Treatment with endothelin-receptor antagonists increases NOS activity in hypercholesterolemia.

In experimental hypercholesterolemia, endothelium-dependent relaxations decrease, as does endothelial immunoreactivity for nitric oxide (NO) synthase (NOS; eNOS) in coronary arteries. Systemic levels of NO also decrease with concomitant elevations in systemic circulating levels of endothelin (ET)-1. Chronic treatment of hypercholesterolemic pigs with ET-receptor antagonists increases circulating NO and improves endothelium-dependent relaxations. Mechanisms causing these increases are not known. Therefore, experiments were designed to test the hypothesis that chronic administration of ET-receptor antagonists to hypercholesterolemic pigs increases NO production through increases in NOS activity. Female juvenile pigs were fed a 2% cholesterol atherogenic diet and were randomly allocated to receive no treatment (controls), a selective ET(A)-receptor antagonist (ABT-624), or a combined ET(A) + ET(B)-receptor antagonist (RO-48-5695) daily for 12 wk. After 12 wk, endothelial cells from thoracic aorta were prepared for measurement of eNOS mRNA or eNOS activity. Total cholesterol, low-density-lipoprotein cholesterol, and concentrations of ET-1 were significantly higher in all three groups at 12 wk compared with baseline levels. Circulating plasma-oxidized products of NO (NOx) increased with ET-receptor blockade. NOS mRNA was similar among groups. Total and Ca-dependent NOS activity was significantly higher in aortic endothelial cells from the ET(A) + ET(B)-treated pigs compared with those treated with ET(A) antagonist alone. These results suggest that changes in systemic NOx after chronic inhibition of ET(A) + ET(B) receptors in hypercholesterolemia may result from posttranscriptional changes in NOS.

Gene transfer of endothelial nitric oxide synthase to pulmonary allografts: impact on acute rejection.

Experiments were designed to study whether overexpression of nitric oxide (NO) from endothelial nitric oxide synthase (eNOS) affects acute rejection. Allogenic, orthotopic single-lung transplantation was performed after transbronchial adenoviral-mediated gene transfer (3 x 10(8) pfu) of either of eNOS or beta-galactosidase to donor lungs of rats (n = 6 each). No immunosuppression was used. After 4 days, transplanted lungs were prepared for enzyme activity, cGMP and histology. Calcium-dependent NOS activity, reflecting eNOS, was greater in eNOS-transduced lungs (587 +/- 97 vs 2.1 +/- 1.4 pmol/mg protein per h, P <0.001). In contrast, calcium-independent NOS activity, reflecting iNOS, was comparable. Concentrations of cGMP were higher in eNOS-transduced lungs (13.2 +/- 2.3 vs 4.9 +/- 0.5 pmol/mg protein). Positive immunostaining for eNOS was present in pneumocytes only in eNOS-transduced lungs. No difference in histological grade of rejection was observed. eNOS gene transfer to pulmonary allografts results in a functionally active transgene product and increased NO production. Increasing NO from eNOS does not affect histogically identified acute rejection.