Phosphatidylethanol Detects Moderate-to-Heavy Alcohol Use in Liver Transplant Recipients.

BACKGROUND: Alcohol-dependent liver transplantation (LT) patients who resume alcohol consumption are at risk for a number of alcohol-related problems including liver injury and liver failure. Post-LT patients are strongly advised to remain abstinent. However, we do not know how well this population complies due to a lack of valid methods (self-report and/or biomarkers) to identify alcohol use. Studies suggest as many as 50% resume alcohol use within 5 years. Phosphatidylethanol (PEth) is a new cell-membrane phospholipid biomarker to identify alcohol use in the past 28 days. This prospective study followed 213 LT recipients at 2 U.S. liver transplant centers. METHODS: Sample included 213 LT subjects; 70.9% (n = 151/213) had a history of alcohol dependence prior to transplantation and 29.1% (n = 62/213) served as non-alcohol-dependent controls. Subjects participated in face-to-face interviews to assess alcohol use using a 30-day calendar. The protocol called for collecting blood samples at baseline, 6-, and 12-month follow-up. RESULTS: Seventy percent (149/213) who reported no alcohol use had consistently negative PEth levels (<8 ng/ml). A total of 26.4% (57/213), 44 alcohol-dependent patients and 13 controls, had a positive PEth test of >8 ng/ml either at baseline and/or during the follow-up period. Alcohol-dependent subjects (23.8%; n = 36/151) and 16.1% (n = 10/62) controls reported no alcohol use but had at least 1 positive PEth test. Of the 11.2% (24/213) post-LT subjects who reported recent alcohol use, over half (11/24) had a positive PEth. The 13 self-reported alcohol users with a negative PEth level reported insufficient drinking to trigger PEth formation. CONCLUSIONS: Adoption of PEth as part of routine posttransplant care of LT recipients will enable early identification of patients at risk of alcohol use and facilitate abstinence in patients with a history of alcohol dependence and alcohol-related liver damage.

Plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation.

UNLABELLED: Biomarkers predictive of recovery from acute kidney injury (AKI) after liver transplantation (LT) could enhance decision algorithms regarding the need for liver-kidney transplantation or renal sparing regimens. Multianalyte plasma/urine kidney injury protein panels were performed immediately before and 1 month post-LT in an initial test group divided by reversible pre-LT AKI (rAKI = post-LT renal recovery) versus no AKI (nAKI). This was followed by a larger validation set that included an additional group: irreversible pre-LT AKI (iAKI = no post-LT renal recovery). In the test group (n = 16), six pre-LT plasma (not urine) kidney injury proteins (osteopontin [OPN], neutrophil gelatinase-associated lipocalin, cystatin C, trefoil factor 3, tissue inhibitor of metalloproteinase [TIMP]-1, and ß-2-microglobulin) were higher in rAKI versus nAKI (P < 0.05) and returned to normal values with renal recovery post-LT. In the validation set (n = 46), a number of proteins were significantly higher in both rAKI and iAKI versus nAKI. However, only pre-LT plasma OPN (P = 0.009) and TIMP-1 (P = 0.019) levels were significantly higher in rAKI versus iAKI. Logistic regression modeling was used to correlate the probability of post-LT rAKI, factoring in both pre-LT protein markers and clinical variables. A combined model including elevated OPN and TIMP-1 levels, age <57, and absence of diabetes had the highest area under the curve of 0.82, compared to protein-only and clinical variable-only models. CONCLUSION: These data suggest that plasma protein profiles might improve the prediction of pre-LT kidney injury recovery after LT. However, multicenter, prospective studies are needed to validate these findings and ultimately test the value of such protein panels in perioperative management and decision making.

Prospective randomized pilot study of Y90+/-sorafenib as bridge to transplantation in hepatocellular carcinoma.

BACKGROUND & AIMS: To investigate the safety and adverse event profile of sorafenib plus radioembolization (Y90) compared to Y90 alone in patients awaiting liver transplantation. METHODS: 20 patients with HCC were randomized to Y90 alone (Group A) or Y90+sorafenib (Group B). Adverse events, dose reductions, and peri-transplant complications were assessed. RESULTS: All patients in the sorafenib group necessitated dose reductions. Seventeen of 20 patients underwent liver transplantation; median time-to-transplant was 7.8 months (range: 4.2-20.3) and similar between groups (p = 0.35). In the sorafenib group, there were 4/8 peri-transplant (<30 days) biliary complications (p = 0.029) and 3/8 acute rejections (p = 0.082); there were none in the Y90-only group. Survival rates were 70% (Group A) and 72% (Group B) at 3 years (p = 0.57). CONCLUSIONS: The addition of sorafenib to Y90 necessitated dose reductions in all patients awaiting transplantation. Preliminary data suggest that the combination was associated with more peri-transplant biliary complications and potentially trended towards more acute rejections. Caution should be exercised when considering sorafenib in the transplant setting. Further investigation is warranted.

Systemic immunoregulatory and proteogenomic effects of tacrolimus to sirolimus conversion in liver transplant recipients.

UNLABELLED: Immunosuppression (IS) withdrawal from calcineurin inhibitors is only possible in ≈ 20% of liver transplant recipients. However, mammalian target of rapamycin inhibitors (e.g., sirolimus; SRL) appear to be more immunoregulatory and might promote a tolerant state for withdrawal. Our aim was to determine whether systemic (i.e., blood, marrow, and allograft) signatures of immunoregulation are promoted by conversion from tacrolimus (TAC) to SRL. We therefore performed the following serial assays before and after SRL conversion in liver transplant recipients to test for enhanced markers of immunoregulation: (1) flow-cytometry immunophenotyping of peripheral blood mononuclear cells (PBMCs) and bone marrow aspirates for regulatory T cells (Tregs) (e.g., CD4(+) CD25(+++) FOXP3(+) ) and regulatory dendritic cells (DCregs) (immunoglobulin-like transcript 3(+) /4(+) ); (2) liver biopsy immunohistochemical staining (e.g., FOXP3:CD3 and CD4:CD8 ratios) and immunophenotyping of biopsy-derived Tregs after growth in culture; (3) effects of pre- versus postconversion sera on Treg generation in mixed lymphocyte reactions; (4) peripheral blood nonspecific CD4 responses; and (5) peripheral blood gene transcripts and proteomic profiles. We successfully converted 20 nonimmune, nonviremic recipients (age, 57.2 ± 8.0; 3.5 ± 2.1 years post-liver transplantation) from TAC to SRL for renal dysfunction. Our results demonstrated significant increases in Tregs in PBMCs and marrow and DCregs in PBMCs (P < 0.01) after conversion. In biopsy staining, FOXP3:CD3 and CD4:CD8 ratios were significantly higher after conversion and a number of biopsy cultures developed new or higher FOXP3(+) cell growth. Nonspecific CD4 responses did not change. Both pre- and postconversion sera inhibited mixed lymphocyte reactions, although only TAC sera suppressed Treg generation. Finally, 289 novel genes and 22 proteins, several important in immunoregulatory pathways, were expressed after conversion. CONCLUSIONS: TAC to SRL conversion increases systemic Tregs, DCregs, and immunoregulatory proteogenomic signatures in liver transplant recipients and may therefore facilitate IS minimization or withdrawal.

The economic impact of MELD on liver transplant centers.

Adoption of the model for end stage liver disease (MELD) system prioritized patients awaiting liver transplant (LT) by severity of illness including progressive renal dysfunction. Unfortunately, current reimbursement for LT is not adjusted by severity of illness or need for simultaneous liver-kidney transplantation (LKT). This study examines hospital cost and reimbursement for LT and LKT to determine the effect of MELD on transplant center (TC) financial outcomes given current reimbursement practices as well as DRG outlier threshold limits. LT was performed for 86 adults prior to and 127 following the implementation of MELD. Between the eras, there was a substantial increase in the average laboratory MELD score (17.1 to 20.7 p=0.004) and percentage of LKTs performed (5.8% to 17.3% p=0.01). Increasing MELD score was associated with higher costs ($4309 per MELD point p<0.001) and decreasing TC net income ($1512 per MELD point p<0.001). In patients not achieving the Medicare outlier status, predicted net loss was $17,700 for high-MELD patients and $19,133 for those needing LKT. In conclusion, contractual reimbursement agreements that are not indexed by severity of disease may not reflect the increased costs resulting from the MELD system. Even with outlier thresholds, Medicare reimbursement is inadequate resulting in a net loss for the TC.

Living donor liver transplant for malignancy.

Adult-to-adult living donor liver transplantation (ALDLT) is being increasingly utilized to treat patients with locally advanced hepatocellular carcinoma and cholangiocarcinoma who are not prioritized under the MELD allocation system. A single institution retrospective chart review examined ALDLTs performed for malignancy to identify indications, complications, and transplant outcome. Since 1997, 18 ALDLTs have been performed for malignancy as the primary indication. Thirteen patients were transplanted for HCC. The median survival following transplant was 18.6 months and four patients developed recurrent HCC. Five patients were transplanted for cholangiocarcinoma, with a 100% recurrence free survival at a mean follow up of 18 months among patients given neo-adjuvant chemoradiation. ALDLT can be safely performed for malignancy with an acceptable peri-operative mortality rate. However, HCC patients with large tumors experience a high rate of recurrence. The use of ALDLT for cholangiocarcinoma appears promising specifically in the context of neo-adjuvant therapy.

Hepatitis C: an update for occupational health nurses.

Hepatitis C is no longer an emerging dilemma. It is a significant public health problem with life altering complications. Occupational health nurses have the responsibility to their employees to be up to date on the latest treatment modalities so they can accurately advise their clients should an exposure occur. Occupational health nursing practice needs to focus on employee education related to Occupational Safety and Health Administration's Blood Borne Pathogens Standard and the latest in safety devices through regular yearly in-services.