Combining ALT/AST Values with Surgical APGAR Score Improves Prediction of Major Complications after Hepatectomy.

Hepatectomy is a complex procedure with high morbidity and mortality. Early prediction/prevention of major complications is highly valuable for patient care. Surgical APGAR score (SAS) has been validated to predict post-surgical complications (PCs). We aimed to define a simple complications classification following hepatectomy based on a therapy-oriented severity Clavien-Dindo classification (CDC). 119 patients undergoing liver resection were included. PCs were determined at follow-up based on CDC. Clinicopathological factors were used to calculate SAS. A receiver-operator characteristic (ROC) curve analysis estimated the predictive value of SAS for PCs. Circulating markers levels of liver injury were analyzed as critical elements on PCs. SAS (P=0.008), estimated blood-loss (P=0.018) and operation time (P=0.0008) were associated with PCs. SAS was reduced in patients with (+) compared to those without (-) complications (6.64±1.84 vs 5.70±1.79, P=0.0079). The area-under-the-curve was 0.646 by ROC, indicating an acceptable discrimination with 65% possibility to distinguish (-) and (+) groups (P=0.004). Best cutoff value for SAS was ≤6/≥7, at which sensitivity and specificity were maximal. ALT/ASL levels were significantly different within the group with 9-10 SAS points (P=0.01 and 0.02). In conclusion, SAS provides accurate risk stratification for major PCs after hepatectomy, and might help improving the overall patient outcome.

The effect of Share 35 on biliary complications: An interrupted time series analysis.

The purpose of the Share 35 allocation policy was to improve liver transplant waitlist mortality, targeting high MELD waitlisted patients. However, policy changes may also have unintended consequences that must be balanced with the primary desired outcome. We performed an interrupted time series assessing the impact of Share 35 on biliary complications in a select national liver transplant population using the Vizient CDB/RM database. Liver transplants that occurred between October 2012 and September 2015 were included. There was a significant change in the incident-rate of biliary complications between Pre-Share 35 (n = 3018) and Post-Share 35 (n = 9984) cohorts over time (P = .023, r2  = .44). As a control, a subanalysis was performed throughout the same time period in Region 9 transplant centers, where a broad sharing agreement had previously been implemented. In the subanalysis, there was no change in the incident-rate of biliary complications between the two time periods. Length of stay and mean direct cost demonstrated a change after implementation of Share 35, although they did not meet statistical difference. While the target of improved waitlist mortality is of utmost importance for the equitable allocation of organs, unintended consequences of policy changes should be studied for a full assessment of a policy's impact.

The Current State of Liver Transplantation in the United States: Perspective From American Society of Transplant Surgeons (ASTS) Scientific Studies Committee and Endorsed by ASTS Council.

This article is a review of the salient points and a future prospective based on the 2014 Organ Procurement and Transplantation Network (OPTN)/Scientific Registry of Transplant Recipients (SRTR) liver donation and transplantation data report recently published by the American Journal of Transplantation. Emphasis of our commentary and interpretation is placed on data relating to waitlist dynamics, organ utilization rates, the impact of recent advances in the treatment of hepatitis C, and the increases in end-stage renal disease among liver transplant candidates. Finally, we share our vision on potential areas of innovation that are likely to significantly improve the field of liver transplantation in the near future.

Clinical outcomes and costs associated with in-hospital biliary complications after liver transplantation: a cross-sectional analysis.

INTRODUCTION: In-hospital biliary complications (BCs) after liver transplantation (LT) are reported in up to 20 % of patients and contribute to poor outcomes and increased costs. Existing single-center outcome and cost analyses studies are limited in scope. METHODS: This is a cross-sectional analysis of national data involving 7,967 patients transplanted between 2011 and 2012 with the primary aim of determining the association between BCs and clinical outcomes and costs. Age, race, diagnosis, and severity of illness are associated with the development of BCs. RESULTS: BCs develop in 14.6 % of LT recipients and have substantial implications for perioperative outcomes, including length of hospital and ICU stay (27.9 vs 19.6 mean days, p < 0.001 and 12.0 vs 8.3 mean days, p < 0.001, respectively), in-hospital morbidity (39 vs 27 %, p < 0.001), 30-day readmissions (14.8 vs 11.2 %, p < 0.001), and in-hospital mortality (5.8 vs 4.0 %, p < 0.001). BCs contributed to a mean increase in in-hospital costs of $36,212 (p < 0.001), due to increases in accommodations ($9,539, p < 0.001), surgical services ($3,988, p < 0.001), and pharmacy services ($8,445, p < 0.001). DISCUSSION: BCs are a predominant etiology for in-hospital morbidity and mortality, while contributing significantly to the high cost of LT. Efforts should be focused on understanding salient and modifiable risk factors, while developing innovative strategies to reduce BCs.

Renal function at two years in liver transplant patients receiving everolimus: results of a randomized, multicenter study.

In a 24-month prospective, randomized, multicenter, open-label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy-proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference -2.2%, 97.5% confidence interval [CI] -8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m(2) (97.5% CI 1.9, 11.4 mL/min/1.73 m(2), p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m(2) in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m(2) in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced-exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

Improving transplant patient safety through pharmacist discharge medication reconciliation.

Greater than 50% of medication errors are estimated to occur during transitions of care, and solid-organ transplant recipients are at an increased risk for errors due to significant changes in their medication regimen following transplantation. This prospective, observational study with a historical control group was conducted to evaluate the discharge process for transplant recipients and determine if transplant pharmacist involvement would improve safety. During the prospective period, a total of 191 errors were made on discharge medication reconciliations (n = 64, mean rate 3.0 per patient); however, pharmacists prevented 119 of these errors (1.9 errors per patient). In the retrospective period, none of the 430 errors identified were prevented at the time of discharge (n = 128, p < 0.0001). The 72 errors not prevented at the time of discharge in the prospective cohort were identified by the pharmacist at the patient's first clinic visit (1.1 errors per patient). In the historical cohort, all 430 errors made at discharge persisted until at least the time of the first clinic visit (3.4 errors per patient, p < 0.0001). This study demonstrates that transplant recipients are at a high risk for medication errors and that transplant pharmacist involvement leads to improved safety through the significant reduction of medication errors.

Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial.

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (-3.0%; 95% CI -8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m(2) , 97.5% CI 3.74, 13.27 mL/min/1.73 m(2) , p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

The impact of early corticosteroid withdrawal on graft survival in liver transplant recipients.

BACKGROUND: There has been increased interest in recent years in reducing or eliminating steroids from the immunosuppression regimen of transplant recipients to reduce adverse effects associated with their use. The purpose of this study was to compare clinical outcomes between early versus late steroid withdrawal after liver transplant to determine the optimal duration of steroid use in this population. METHODS: This large-scale, retrospective analysis of liver transplants occurred at our institution between 2000 and 2009. Patients were excluded if they were <18 years old, received a multiorgan transplant, or remained on steroids for >1 year. The early steroid withdrawal group had steroids eliminated by 3 months posttransplant; late steroid withdrawal patients had steroids withdrawn between 3 and 12 months posttransplant. RESULTS: A total of 586 liver transplants occurred during the study period; 330 patients were included in the analysis. Graft survival was significantly lower in the early steroid withdrawal group. There was no difference in patient survival or overall acute rejection. However, the late steroid withdrawal group had a significantly higher rate of early acute rejection episodes. There was no difference with regard to new-onset diabetes after transplant, hyperlipidemia, or cardiovascular events between groups. CONCLUSION: The results of this study suggest that late corticosteroid withdrawal is associated with better long-term graft survival without increasing the rates of diabetes, hyperlipidemia, or cardiovascular events in liver transplant recipients. A prospective study is warranted to confirm these findings.

A critical analysis of racial difference with mycophenolate mofetil (MMF) dosing, clinical outcomes and adverse effects in pediatric kidney transplant patients.

There is paucity in the data examining the differences in mycophenolate mofetil (MMF) dosing and outcomes among pediatric kidney transplant recipients (PKTX) between races. The aims of this study were as follows (i) to assess whether higher doses of MMF are being utilized in African American (AA) PKTX (ii) to determine whether there is a correlation between MMF dose and outcomes between races, and (iii) to assess the adverse effects of MMF between races. This study analyzed 109 PKTX who received MMF between 7/99 and 5/08. Demographics were similar between groups. Fewer AAs received kidneys from living donors (18% vs. 44%), spent more time on dialysis (1.0 vs. 0.5 yr), and had more human leukocyte antigen mismatches (4 vs. 3). MMF doses among AA patients were higher throughout the study, with statistical differences at week 4, month 3, and month 18. AA patients had significantly higher acute rejection rates and trended toward poorer graft survival; infections, adverse events from MMF and post-transplant lymphoproliferative disease tended to be lower in the AA patients. AA PKTX received higher MMF doses within the first three yr post-transplant compared to their non-AA counterparts, yet demonstrate significantly more acute rejection episodes. Importantly, MMF caused fewer adverse events in AA patients, despite these patients receiving higher doses.

Potential differences in kidney allograft outcomes between ethnicities when converting to sirolimus base immunosuppression.

OBJECTIVE: The aim of this study was to determine whether ethnicity impacts graft outcomes in kidney transplant patients converted to sirolimus (SRL) and maintained on either calcineurin inhibitors (CI) or mycophenolate mofetil (MMF) with steroids. METHODS: This study analyzed kidney transplants converted to SRL and transplanted between July 1991 and April 2007. Patients were divided into 4 groups: group 1: African-Americans converted to SRL + CI; group 2: non-African-Americans converted to SRL + CI; group 3: African-Americans converted to SRL + MMF; group 4: non-African-Americans converted to SRL + MMF. RESULTS: A total of 242 patients was included. Demographics, baseline immunosuppression, and reason for SRL conversion were similar among groups. Patients converted to SRL + CI regimens had significantly higher rates of acute rejection before SRL conversion, but equal rates after conversion. Development of proteinuria was similar across groups. African-American patients converted to SRL + MMF tended to have poorer outcomes compared with African-American patients converted to SRL + CI. Non-African-American patients converted to SRL + MMF tended to have better graft outcomes compared with non-African-American patients converted to SRL + CI. CONCLUSIONS: African-Americans converted to SRL may benefit from continued CI, whereas non-African-Americans converted to SRL seem to have better outcomes with MMF. Further prospective studies are warranted to confirm these findings.

The use of drotrecogin alfa (activated) in solid organ transplant patients: a case series.

BACKGROUND: Drotrecogin alfa (activated) (DAA), a recombinant human activated protein C, is indicated for the reduction of mortality in patients with severe sepsis who have a high risk of death. In the initial trial, DAA demonstrated a significant reduction in mortality at 28 days for patients treated with DAA in comparison with standard supportive treatment (placebo). However, solid organ transplant recipients were excluded from the study. Transplant recipients are at an increased risk for sepsis and there is minimal literature describing the safety and efficacy of DAA in the transplant population. METHODS: Thirteen solid organ transplant recipients who received DAA between November 2001 and January 2004 were included in this case series. Patients were prospectively identified and data collection occurred concurrently and by retrospective chart review. All patients met the DAA use criteria based on the institutional standard protocol. RESULTS: We report the outcomes of the 13 adult transplant patients who received a total of 14 courses of DAA for severe sepsis. At the time of DAA initiation, all patients required mechanical ventilation, 86% necessitated vasopressor support, and had a median of 3 dysfunctional organs. The median Acute Physiology and Chronic Health Evaluation (APACHE) II score at initiation was 30. Overall, hemodynamic stability and APACHE II score improved at the end of DAA infusion. Causes of early discontinuation were bleeding (57%), scheduled procedure (14%), increased international normalized ratio (14%), and death (14%). In-hospital, 28-day, and 1-year mortality was 69%, 62%, and 83%, respectively. CONCLUSION: DAA appears to be safe with appropriate monitoring. However, transplant recipients had a higher incidence of bleeding events leading to early discontinuation of DAA. Efficacy is difficult to assess without an appropriate control group for comparison.

Long-term efficacy of induction therapy with anti-interleukin-2 receptor antibodies or thymoglobulin compared with no induction therapy in renal transplantation.

BACKGROUND: Although the utility of antibody induction therapy has been demonstrated in clinical trials, the ideal regimen to use based on patient risk factors has not been fully elucidated. The objectives of this study were to determine the impact of either anti-interleukin-2 receptor antibodies (IL-2RA) or thymoglobulin induction therapies versus no induction therapy on acute rejection rates and on 3-year graft survival rates. METHODS: This retrospective analysis compared 3 patient groups-those who did not receive induction, those who received IL-2RA induction, and those who received thymoglobulin induction. RESULTS: Three hundred eleven patients were included in this study. Patients were well matched for demographic and immunologic characteristics in the noninduced and IL-2RA induction therapy groups; the thymoglobulin induction group included significantly higher risk patients. The acute rejection rates were significantly lower in the IL-2RA and thymoglobulin groups when compared with the no induction therapy group (28% vs 15% vs 41%, respectively; P = .001), which was confirmed with multivariate analysis. The 3-year graft loss rates (no induction 21% vs IL2-RA induction 19% vs thymoglobulin induction 25%; P > .50) and creatinine concentrations (no induction 1.8 +/- 0.7, IL-2RA induction 2.0 +/- 1.0, and thymoglobulin induction 1.9 +/- 1.2; P = .47) were similar between all groups. CONCLUSION: The use of induction therapy significantly reduces the incidence of acute rejection. The use of thymoglobulin induction equalizes 3-year graft survival rates in high-risk patients to those seen in low-risk patients receiving either no induction or IL-2RA induction.

C-Jun N-terminal kinase 2 promotes graft injury via the mitochondrial permeability transition after mouse liver transplantation.

The c-Jun N-terminal kinase (JNK) pathway enhances graft injury after liver transplantation (LT). We hypothesized that the JNK2 isoform promotes graft injury via the mitochondrial permeability transition (MPT). Livers of C57BL/6J (wild-type, WT) and JNK2 knockout (KO) mice were transplanted into WT recipients after 30 h of cold storage in UW solution. Injury after implantation was assessed by serum ALT, histological necrosis, TUNEL, Caspase 3 activity, 30-day survival, and cytochrome c and 4-hydroxynonenal immunostaining. Multiphoton microscopy after LT monitored mitochondrial membrane potential in vivo. After LT, ALT increased three times more in WT compared to KO (p < 0.05). Necrosis and TUNEL were more than two times greater in WT than KO (p < 0.05). Immunostaining showed a >80% decrease of mitochondrial cytochrome c release in KO compared to WT (p < 0.01). Lipid peroxidation was similarly decreased. Every KO graft but one survived longer than all WT grafts (p < 0.05, Kaplan-Meier). After LT, depolarization of mitochondria occurred in 73% of WT hepatocytes, which decreased to 28% in KO (p < 0.05). In conclusion, donor JNK2 promotes injury after mouse LT via the MPT. MPT inhibition using specific JNK2 inhibitors may be useful in protecting grafts against adverse outcomes from ischemia/reperfusion injury.

Can family attributes explain the racial disparity in living kidney donation?

BACKGROUND: Living donation is a safe, effective treatment for patients with end-stage renal disease (ESRD), yet rates of live kidney donation remain low. Potential transplant recipients may be more inclined to ask a family member for a living donation if they feel familial closeness. METHODS: The FACES II and the Living Organ Donor Survey were administered to patients attending pretransplant education to assess individual perceptions of family structure and willingness to request a living kidney donation from a family member. RESULTS: A total of 328 potential transplant recipients were included in the study: 200 (61%) African American and 128 (39%) Caucasian. Approximately half were willing to ask for a living donation. Individual's perception of family cohesion, adaptability, and type as measured by FACES II showed most families were mid-range with optimal cohesion and adaptability. Family cohesion and adaptability showed no association with being willing to request a live donation, but those single/never married were only half as likely to ask for donation (odds Ratio [OR] 0.51; 95% confidence interval [CI] 0.31-0.86, P = .01). Lower education (beta = -0.49) and unmarried status (beta = -0.31) predicted a lower cohesion score. CONCLUSION: Family type, cohesion, and adaptability showed no differences across race and was not related to the potential recipient's willingness to ask for a live donation. Although responses by race did not differ, an important finding showed that only half of ESRD patients are willing to ask for a live organ donation, and those patients that were single/never married were less likely to ask for a living donation. Research surrounding this reluctance is warranted.

Parenchymal transection of the kidney inflicted by endocatch bag entrapment during a laparoscopic donor nephrectomy.

We present a case of inadvertent decapsulation and grade IV renal parenchyma laceration during laparoscopic donor nephrectomy. The kidney was repaired, used and functioned immediately. There were no complications in the donor. To our knowledge, this type of injury has not been reported previously and the purpose of this report is to focus attention on the potential for this unusual injury, which can occur during delivery of the kidney using the endocatch bag.

Valganciclovir prophylaxis in patients at high risk for the development of cytomegalovirus disease.

BACKGROUND: Despite advances in antiviral therapies, cytomegalovirus (CMV) remains the leading opportunistic infection in the transplant population. Valganciclovir (VGC), the L-valyl ester prodrug of ganciclovir (GCV), provides an excellent oral alternative to GCV for the prevention of CMV in transplant recipients. We investigated the use of VGC for CMV prevention in high-risk renal and pancreas transplant recipients. METHODS: Patients at high risk for development of CMV disease were defined as either those who had donor positive, recipient-negative serostatus (D+/R-), or those who received antilymphocyte antibody (ALA) therapy for either rejection treatment or induction. A retrospective review was conducted of all kidney and pancreas transplants performed between August 2001 and December 2003. A total of 341 transplants were performed, of which 109 received VGC, and 88 were included in this analysis. RESULTS: The overall incidence of CMV disease was 5.7% (5/88). All of the CMV episodes were in patients who were D+/R- (17.2% [5/29] versus 0% [0/59], P<0.001). Of these patients, all the episodes of CMV were in patients who received VGC prophylaxis for<100 days post transplant (29% [5/17] versus 0% [0/12], P=0.06). The overall incidence of leukopenia was 11% and thrombocytopenia was 7%, with the incidence between the D+/R- group and the ALA group being similar. CONCLUSION: VGC is an effective agent in preventing CMV disease in kidney and pancreas transplant recipients who are at high risk for developing the disease. The optimal length of prophylaxis in D+/R- patients is still undefined, while 3 months of prophylaxis appears to be sufficient in patients who received ALA therapy.

Does treatment of cadaveric organ donors with desmopressin increase the likelihood of pancreas graft thrombosis? Results of a preliminary study.

Desmopressin (DDAVP) is commonly used in cadaveric organ donors to treat diabetes insipidus. The thrombogenic potential of DDAVP is well known. Recent animal data have demonstrated that DDAVP impairs pancreas graft (PG) microcirculation and perfusion. The aim of this study was too evaluate the effect of DDAVP on the incidence of PG thrombosis in clinical pancreas transplantation. A retrospective review of simultaneous kidney-pancreas transplant (SKPT) entered in the Scientific Registry of Transplant Recipients (SRTR) between 10/5/87 and 9/27/02 was performed. Patients were included for analysis if there was definitive documentation as to whether DDAVP was (DDAVP-Y) or was not (DDAVP-N) administered to the donor. Both dose and duration of DDAVP treatment were not recorded by SRTR. A total of 2804 SKPTs were available for analysis. Mean follow-up was 1.75 years (range, 1 month to 8.4 years). A total of 1287 SKPT patients (46%) received a PG from a DDAVP-Y donor. Graft ischemia times, donor and recipient ages, recipient gender distribution, surgical techniques, and immunosuppressive regimens were similar in both groups. The overall incidence of PG thrombosis was 4.3%. The incidence of PG thrombosis in recipients of grafts from DDAVP-Y donors was 5.1% compared to 3.5% in recipients of grafts from DDAVP-N donors (P =.04). Fifty-eight percent of thrombosed PG came from DDAVP-Y donors compared to 42% from DDAVP-N donors (P =.04). We conclude that there appears to be a relationship between donor treatment with DDAVP and PG thrombosis. A prospective study is needed to verify these findings and to determine their clinical significance.

Long-term outcome of sirolimus rescue in kidney-pancreas transplantation.

The aim of this study was to evaluate long-term outcome of sirolimus (SRL) rescue in kidney-pancreas transplantation (KPTx). We reviewed 112 KPTx performed at our institution from 12/3/95 to 6/27/02. All patients received antibody (Ab) induction, tacrolimus (TAC), mycophenolate mofetil (MMF), and steroids. Thirty-five patients (31%) had SRL substituted for MMF for the following indications: (1) acute rejection (AR) of kidney or pancreas despite adequate TAC levels; (2) intolerance of full-dose MMF; (3) rising creatinine; and (4) TAC-induced hyperglycemia. Target SRL and TAC levels were 10 ng/mL and 5 ng/mL, respectively. Mean follow-up was 3 +/- 2 years overall and 1.2 +/- 0.5 years after SRL rescue. No patients died. One- and 3-year actuarial kidney and pancreas graft survival was 97%, 97%, and 95%, 90%, respectively. Of 10 patients switched to SRL for AR, 1 kidney failed from Ab-resistant AR, 1 kidney developed borderline AR, and the other 8 remain AR-free. Seven other patients developed AR despite therapeutic SRL levels; of these, 6 (86%) had mean TAC levels of <4.5 in the month preceding AR. Mean creatinine overall and for the rising creatinine group remained stable. All patients switched to SRL for TAC-induced hyperglycemia or MMF intolerance demonstrated biochemical or clinical improvement. Sirolimus-related infection or other serious adverse events (SAE) were uncommon. In conclusion, KPTx recipients can be safely switched to SRL with long-term stabilization of renal function, excellent graft and patient survival, and no increase in SAE. A minimum TAC level of 4.5 ng/mL may be necessary to prevent late AR.