Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.

The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; ≤Stage 2 Ishak fibrosis; and absence of rejection on biopsy. Immunosuppression withdrawal followed an 8-step reduction algorithm with ≥8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to ≤50% of baseline dose, and 10 of 77 (13.0%) discontinued all immunosuppression for ≥1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage ≥3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.

Complete Chain of the First Global Kidney Exchange Transplant and 3-yr Follow-up.

BACKGROUND: Global Kidney Exchange (GKE) offers an opportunity to expand living renal transplantation internationally to patients without financial means. These international pairs are entered into a US kidney exchange program that provides long-term financial support in an effort to identify opportunities for suitable exchanges for both these international pairs and US citizens. OBJECTIVE: While the promise of GKE is significant, it has been met with ethical criticism since its inception in 2015. This paper aims to demonstrate the selection process and provide >3 yr of follow-up on the first GKE donor and recipient from the Philippines. DESIGN, SETTING, AND PARTICIPANTS: The first GKE transplant occurred with a young Filipino husband and wife who were immunologically compatible, but lacked the financial means to continue hemodialysis or undergo a kidney transplant in their home country. The pair was enrolled in the Alliance for Paired Donation matching system, several alternative kidney exchanges were identified, and the pair subsequently underwent renal transplantation and donation in the USA financed by philanthropy. The resulting nonsimultaneous extended altruistic chain provided transplantation for the Filipino husband and 11 US patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Filipino donor and recipient were followed by transplant professionals in both the Philippines and the USA. Follow-up data were maintained as required by the Organ Procurement and Transplantation Network in the USA. RESULTS AND LIMITATIONS: The Filipino donor has normal blood pressure and renal function, and the Filipino recipient is doing well 3.5 yr after their donation and transplantation. CONCLUSIONS: While criticisms of GKE highlight concerns for possible exploitation of financially disadvantaged groups, these results demonstrate that these concerns did not come to fruition, and the outcome experienced by the GKE donor and recipient (and other US participants) was successful. PATIENT SUMMARY: The first Filipino Global Kidney Exchange (GKE) donor-recipient pair continues to be followed by both US and Filipino transplant centers. Both are in good health, support the GKE program, and advocate for its expansion.

Successful Porcine Renal Transplantation After 60 Minutes of Donor Warm Ischemia: Extracorporeal Perfusion and Thrombolytics.

Donation from uncontrolled circulatory determination of death donors (uDCD) is impractical in United States because of the time needed to organize procurement before irreversible organ damage. Salvaging organs after prolonged warm ischemic time (WIT) may address this limitation. We evaluated the combination of extracorporeal support (ECS) and thrombolytics in a porcine uDCD renal transplant model. Nonanticoagulated uDCD sustained 60 min of WIT, and two groups were studied. Rapid recovery (RR)-uDCD renal grafts procured using the standard quick topical cooling and renal flush, and ECS-assisted donation (E-uDCD), 4 hr ECS plus thrombolytics for in situ perfusion before procurement. All kidneys were flushed and cold stored, followed by transplantation into healthy nephrectomized recipients without immunosuppression. Delayed graft function (DGF) was defined as creatinine more than 5.0 mg/dl on any postoperative day. Twelve kidneys in E-uDCD and 6 in RR-uDCD group were transplanted. All 12 E-uDCD recipients had urine production and adequate function in the first 48 hr, but two grafts (16.7%) had DGF at 96 hr. All six recipients from RR-uDCD group had DGF at 48 hr and were killed. Creatinine and blood urea nitrogen (BUN) levels were significantly lower in E-uDCD compared with RR-uDCD group at 24 hr (2.9 ± 0.7 mg/dl vs. 5.2 ± 0.9 mg/dl) and 48 hr (3.2 ± 0.9 mg/dl vs. 7.2 ± 1.0 mg/dl); BUN levels at 24 and 48 hr were 28.3 ± 6.7 mg/dl vs. 39.5 ± 7.5 mg/dl and 23.9 ± 5.0 mg/dl vs. 46 ± 12.9 mg/dl, respectively. Thrombolytics plus ECS precondition organs in situ yielding functional kidneys in a porcine model of uDCD with 60 min of WIT. This procurement method addresses logistical limitations for uDCD use in the United States and could have a major impact on the organ donor pool.

Donation after circulatory determination of death: the university of michigan experience with extracorporeal support.

BACKGROUND: Extracorporeal support (ECS) during organ procurement from donors after circulatory determination of death (DCDD) could increase the number of donor organs and decrease posttransplant complications. This study reports the experience of a large transplant center with controlled DCDD. METHODS: A retrospective review of all potential controlled-DCDD cases between October 1, 2000 and July 31, 2013 was performed. We focused on methods, ethical and practical issues, and recipient outcome data of organs procured and transplanted in our institution using ECS-assisted DCDD (E-DCDD). RESULTS: ECS was used for organ procurement in 37 controlled DCDD. The number of organs procured per donor was 2.59, and the number of organs transplanted per donor was 1.68. Delayed graft function occurred in 31% of renal grafts. In three donors (8%), organ donation was not completed because of surgeon judgment. Forty-eight renal grafts (65.8%), thirteen livers (61.9%), and one pancreas (50%) were successfully transplanted. CONCLUSIONS: ECS can be routinely implemented in controlled DCDD. In our experience, the organs provided per donor was 2.59. Widely applied, EDCDD could result in more donor organs, especially when applied to DCDD in uncontrolled conditions.

A prospective, randomized trial of complete avoidance of steroids in liver transplantation with follow-up of over 7 years.

OBJECTIVES: Steroids are a mainstay of treatment in orthotopic liver transplantation (OLT) and are associated with significant morbidity. This trial was conducted to assess the efficacy of steroids avoidance. METHODS: Patients undergoing OLT between June 2002 and April 2005 were entered into a prospective, randomized trial of complete steroids avoidance and followed until November 2011. Recipients received either standard therapy (n = 50) or complete steroids avoidance (n = 50). Analyses were performed on an intention-to-treat basis. The mean follow-up of all recipients was 2095 ± 117 days. Sixteen (32%) recipients randomized to the steroids avoidance group ultimately received steroids for clinical indications. RESULTS: Incidences of diabetes and hypertension prior to or after OLT were similar in both groups, as was the incidence of rejection. Patient and graft survival rates at 1, 3 and 5 years were lower in the steroids avoidance group than in the standard therapy group (patient survival: 1-year, 80% versus 86%; 3-year, 68% versus 76%; 5-year, 60% versus 72%; graft survival: 1-year, 76% versus 76%; 3-year, 64% versus 74%; 5-year, 56% versus 72%), but the differences were not statistically different. CONCLUSIONS: Complete steroids avoidance provides liver transplant recipients with minimal benefit and appears to result in a concerning trend towards decreased graft and recipient survival. The present data support the use of at least a short course of steroids after liver transplantation.

Timing of heparin and perfusion temperature during procurement of organs with extracorporeal support in donors after circulatory determination of death.

Despite successful resuscitation of donors after circulatory determination of death (DCD) with extracorporeal support (ECS), the technique is limited by ethical concerns about donor management (heparinization) and the complexity to operate the ECS circuit. This work studies different timing of heparin administration and the effects of ECS-perfusion temperature. Cardiac arrest (CA) was induced in swine. Heparin studies, three groups: 1) PRE5, heparin 5 minutes before CA; 2) POST5, heparin 5 minutes after CA, plus 2 minutes external chest compressions; and 3) POST30, heparin with the initiation of ECS after 30 minutes CA. Perfusion temperature study, two groups: 1) normothermic, ECS-38.5°C after 30 minutes CA and 2) room temperature, ECS-25.5°C for the first 90 minutes, followed by ECS-38.5°C. Heparin studies: ECS target flows (>50 ml/kg/min) were not achieved in the POST30 group, affecting local organ perfusion as observed with poor bile (<4 ml/min) and urine output (<25 ml/min), when compared with the other groups (normal values). Temperature study: In both groups, ECS target flows were reached, and urine/bile output was restored. Heparinization 5 minutes after CA is equivalent to premortem heparinization in this ECS-DCD model. Heparinization after CA could reduce ethical concerns. Donors after circulatory determination of death were successfully resuscitated at both temperatures, suggesting that the heat exchanger/water heater can be removed to simplify the ECS circuit.

Portal vein thrombosis and survival in patients with cirrhosis.

The effects of occlusive portal vein thrombosis (PVT) on the survival of patients with cirrhosis are unknown. This was a retrospective cohort study at a single center. The main exposure variable was the presence of occlusive PVT. The primary outcome measure was time-dependent mortality. A total of 3295 patients were analyzed, and 148 (4.5%) had PVT. Variables independently predictive of mortality from the time of liver transplant evaluation included age [hazard ratio (HR), 1.02; 95% confidence interval (CI), 1.01-1.03], Model for End-Stage Liver Disease (MELD) score (HR, 1.10; 95% CI, 1.08-1.11), hepatitis C (HR, 1.44; 95% CI, 1.24-1.68), and PVT (HR, 2.61; 95% CI, 1.97-3.51). Variables independently associated with the risk of mortality from the time of liver transplant listing included age (HR, 1.02; 95% CI, 1.01-1.03), transplantation (HR, 0.65; 95% CI, 0.50-0.81), MELD (HR, 1.08; 95% CI, 1.06-1.10), hepatitis C (HR, 1.50; 95% CI, 1.18-1.90), and PVT (1.99; 95% CI, 1.25-3.16). The presence of occlusive PVT at the time of liver transplantation was associated with an increased risk of death at 30 days (odds ratio, 7.39; 95% CI, 2.39-22.83). In conclusion, patients with cirrhosis complicated by PVT have an increased risk of death.

Organ donation after cardiac determination of death (DCD): a swine model.

Donors after Cardiac Death (DCD) may reduce the organ scarcity; however, their use is limited because of warm ischemia time. Fortunately, this is less important in a subclass of DCD called expected (e-DCD), those with irreversible but incomplete brain injury. This study analyzed hemodynamic/pulmonary data to establish a clinically relevant model of cardiac death that would simulate an e-DCD setting. Hemodynamics, pulmonary artery flows, arterial blood gasses, and left atrial pressure were recorded q 5 minutes in anesthetized swine. After baseline data collection, the ventilator was discontinued and heparin was administered. Cardiac death was defined: as asystole, or mean arterial presusure < or = 25 mm Hg with a pulse pressure < or = 20 mm Hg. The time to death was approximately 14.8 minutes. Within 5 minutes of removal of the ventilator, there was a hyperdynamic period. Blood gases throughout the apneic time showed a rapid hypercapnia and acidosis. The hyperdynamic reflex response was followed by hypotension, bradycardia, and finally asystole or ventricular fibrillation. The protocol of withdrawal of ventilation, systemic anticoagulation, determination of death was developed to closely resemble the clinical e-DCD scenario. The physiologic changes that happen before death in DCD were described. An e-DCD model that can be used in studies related to organ transplantation was established.

An intention-to-treat analysis of liver transplantation for hepatocellular carcinoma using organ procurement transplant network data.

Single-center studies have shown acceptable long-term outcomes following orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) when tumors are within the Milan criteria. However, the overall survival and waiting list removal rates have not been described at a national level with pooled registry data. To evaluate this, a retrospective cohort of patients listed for OLT with a diagnosis of HCC between January 1998 and March 2006 was identified from Organ Procurement Transplant Network data. Analysis was performed from the time of listing. Adjusted Cox models were used to assess the relative effect of potential confounders on removal from the waiting list as well as survival from the time of wait listing. A total of 4482 patients with HCC were placed on the liver waiting list during the study period. Of these, 65% underwent transplantation, and 18% were removed from the list because of tumor progression or death. The overall 1- and 5-year intent-to-treat survival for all patients listed was 81% and 51%, respectively. The 1- and 5-year survival was 89% and 61% for those listed with tumors meeting the Milan criteria versus 70% and 32% for those exceeding the Milan criteria (P < 0.0001). On multivariate analysis, advanced liver failure manifested by Child-Pugh class B or C increased the risk of death, while age < 55 years, meeting the Milan criteria, and obtaining a liver transplant were associated with better survival. The current criteria for liver transplantation of candidates with HCC lead to acceptable 5-year survival while limiting the dropout rate. Liver Transpl 15:859-868, 2009. (c) 2009 AASLD.

Biliary complications following liver transplantation in the model for end-stage liver disease era: effect of donor, recipient, and technical factors.

Biliary complications remain a significant problem following liver transplantation in the Model for End-Stage Liver Disease (MELD) era. We hypothesized that donor, recipient, and technical variables may differentially affect anastomotic biliary complications in MELD era liver transplants. We reviewed 256 deceased donor liver transplants after the institution of MELD at our center and evaluated these variables' association with anastomotic biliary complications. The bile leak rate was 18%, and the stricture rate was 23%. Univariate analysis revealed that recipient age, MELD, donor age, and warm ischemia were risk factors for leak, whereas a Roux limb or stent was protective. A bile leak was a risk factor for anastomotic stricture, whereas use of histidine tryptophan ketoglutarate (HTK) versus University of Wisconsin (UW) solution was protective. Additionally, use of a transcystic tube/stent was also protective. Multivariate analysis showed that warm ischemia was the only independent risk factor for a leak, whereas development of a leak was the only independent risk factor for a stricture. HTK versus UW use and transcystic tube/stent use were the only independent protective factors against stricture. Use of an internal stent trended in the multivariate analysis toward being protective against leaks and strictures, but this was not quite statistically significant. This represents one of the first MELD era studies of deceased donor liver transplants evaluating factors affecting the incidence of anastomotic bile leaks and strictures. Donor, recipient, and technical factors appear to differentially affect the incidence of anastomotic biliary complications, with warm ischemia, use of HTK, and use of a stent emerging as the most important variables.

Effect of body mass index on the survival benefit of liver transplantation.

Obese patients are at higher risk for morbidity and mortality after liver transplantation (LT) than nonobese recipients. However, there are no reports assessing the survival benefit of LT according to recipient body mass index (BMI). A retrospective cohort of liver transplant candidates who were initially wait-listed between September 2001 and December 2004 was identified in the Scientific Registry of Transplant Recipients database. Adjusted Cox regression models were fitted to assess the association between BMI and liver transplant survival benefit (posttransplantation vs. waiting list mortality). During the study period, 25,647 patients were placed on the waiting list. Of these, 4,488 (17%) underwent LT by December 31, 2004. At wait-listing and transplantation, similar proportions were morbidly obese (BMI>or=40; 3.8% vs. 3.4%, respectively) and underweight (BMI<20; 4.5% vs. 4.0%, respectively). Underweight patients experienced a significantly higher covariate-adjusted risk of death on the waiting list (hazard ratio [HR]=1.61; P<0.0001) compared to normal weight candidates (BMI 20 to <25), but underweight recipients had a similar risk of posttransplantation death (HR=1.28; P=0.15) compared to recipients of normal weight. In conclusion, compared to patients on the waiting list with a similar BMI, all subgroups of liver transplant recipients demonstrated a significant (P<0.0001) survival benefit, including morbidly obese and underweight recipients. Our results suggest that high or low recipient BMI should not be a contraindication for LT.

Is routine ureteral stenting cost-effective in renal transplantation?

PURPOSE: Recent collective reviews show that ureteral stenting provides a decrease in ureteroneocystostomy anastomotic complications following renal transplantation. We identified the specific morbidity associated with urinary complications following renal transplantation and quantified the health care resources required to treat these patients at a high volume center. MATERIALS AND METHODS: Prospective databases were used to identify patients with a renal transplant who had urinary complications and track postoperative hospital readmissions and admission diagnostic codes. Financial models were used to estimate the variable direct costs of prophylactic stent placement and removal. Cost based analysis was performed to assess the financial feasibility of routine stenting following renal transplantation. RESULTS: Patient specific morbidity and hospital readmissions were significantly increased in patients with a transplant who had a urinary complication. The incremental hospital costs incurred in a patient with a renal transplant who had urinary leakage during the first 12 months postoperatively was $20,121. Routine placement of an anastomotic stent was inexpensive. Approximately 22 or 23 stents could be placed at the same incremental cost of treating 1 patient with a urinary complication in the hospital. CONCLUSIONS: Urinary anastomotic complications following renal transplantation are highly morbid. Even with modest decreases in urinary complications prophylactic ureteral stent placement is financially advantageous.

Early pancreas transplant outcomes with histidine-tryptophan-ketoglutarate preservation: a multicenter study.

Little is known about the use of histidine-tryptophan-ketoglutarate (HTK) preservation solution for pancreas preservation. We compared early pancreas graft outcomes at four pancreas transplant programs within the state of Michigan in 2002 and 2003 (University of Wisconsin [UW] era) with those in 2004 (HTK era). The primary endpoint was early graft loss. The UW group (n=41) and the HTK group (n=36) had similar outcomes with respect to: technical graft loss (9.8% vs. 8.3%, P=NS), 90-day graft function (90.2% vs. 86.1%, P=NS), and rate of pancreatic leak/abscess (12.2% vs. 11.1%, P=NS). There were also no significant differences in postoperative amylase and lipase levels between the two groups. The HTK group did have significantly more acute rejection within the first 180 days (25.0% vs. 9.8%, P<0.05). HTK is a suitable substitute for UW in the preservation of pancreas allografts.

Vancomycin-resistant enterococcal colonization and infection in liver transplant candidates and recipients: a prospective surveillance study.

BACKGROUND: Vancomycin-resistant enterococcal (VRE) infections cause significant morbidity and mortality among patients undergoing liver transplantation. We performed a prospective study among patients awaiting transplantation to assess rates, risk factors, and outcomes associated with VRE colonization before and after transplantation. METHODS: All adults on the transplantation waiting list from 2000-2003 were eligible. Demographic, historical, and laboratory data, as well as stool samples to be analyzed for VRE, were collected at enrollment and every 4-6 months thereafter until transplantation. After transplantation, samples were obtained every 3 days during hospitalization and were analyzed for VRE; outcomes were assessed at 90 days. RESULTS: Overall, 375 patients were enrolled in our study, and 142 received transplants. VRE colonization occurred in 50 (13%) of 375 patients before transplantation and was independently associated with treatment with antianaerobic antimicrobials, third-generation cephalosporins, proton pump inhibitors, or neomycin; having a recent endoscopic retrograde cholangiopancreatogram or paracentesis procedure; and admission to the liver unit. Of these 50 patients, 22 (44%) received a transplant, and 7 (32%) of 22 developed a VRE infection after transplantation. An additional 22 patients (18%) who were not colonized before transplantation acquired VRE after transplantation; VRE infection developed in 5 (23%) of these patients. Patients colonized with VRE either before or after transplantation had longer stays in the intensive care unit and the hospital. Mortality at 90 days was significantly greater among those who acquired VRE after transplantation (5 [23%] of 22), compared with those who had VRE colonization before transplantation (2 [9%] of 22). CONCLUSIONS: Liver transplantation candidates with VRE colonization before transplantation experience greater morbidity but not greater mortality, compared with noncolonized candidates. Transplant recipients who acquire VRE after transplantation have a higher mortality rate than noncolonized recipients. Strategies should be implemented to reduce nosocomial VRE acquisition after transplantation among this vulnerable group.

Extracorporeal support for organ donation after cardiac death effectively expands the donor pool.

BACKGROUND: We sought to evaluate the effect on short-term outcomes of normothermic, extracorporeal perfusion (ECMO) for donation of abdominal organs for transplantation after cardiac death (DCD). Study parameters included increase in number of donors and organs, types of organs procured, and viability of kidneys transplanted. METHODS: We retrospectively reviewed medical record data for all patients enrolled in our ECMO-supported DCD donor protocol between 10/1/2000 to 2/01/2004. We also reviewed the records for all patients undergoing organ donation after brain-death (DBD) during the study period at our institution. Recipient data were obtained and analyzed for all kidneys procured from both groups. RESULTS: Twenty patients were enrolled in our DCD protocol and underwent attempted organ donation. Fifteen patients completed the protocol; 3 maintained cardiac function throughout the prescribed 60 minutes after withdrawal of life support, and two patients' organs were deemed unsuitable for transplantation. Fourteen (70%) of the DCD donor patients originated on the trauma service and six (30%) were from other clinical services. The DCD program increased the potential donor pool by 33% (61 versus 81 patients) and the number of kidneys transplanted by 24% (100 versus 124). A total of 24 kidney, 5 liver, and 1 pancreas transplants were performed with these organs. Two of 24 (8.3%) DCD kidneys had delayed graft function. There were no perioperative rejection episodes or deaths. CONCLUSION: The implementation of a DCD protocol using extracorporeal perfusion increased the potential organ donor pool at our institution by 33%. This was accomplished without short term adverse effect on organ function compared with kidneys transplanted from DBD donors.

Hepatitis C is a risk factor for death after liver retransplantation.

Retransplantation for liver allograft failure associated with hepatitis C virus (HCV) has been increasing due to nearly universal posttransplant HCV recurrence and has been demonstrated to be associated with poor outcomes. We report on the risk factors for death after retransplantation among liver recipients with HCV. A retrospective cohort of liver transplant recipients who underwent retransplantation between January 1997 and December 2002 was identified in the Scientific Registry of Transplant Recipients database. Cox regression was used to assess the relative effect of HCV diagnosis on mortality risk after retransplantation and was adjusted for multiple covariates. Of 1,718 liver retransplantations during the study period, 464 (27%) were associated with a diagnosis of HCV infection. Based on Cox regression, retransplant recipients with HCV had a 30% higher covariate-adjusted mortality risk than those without HCV diagnosis (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.10-1.54; P = 0.002). Other covariates associated with significant relative risk of death after retransplantation included older recipient age, presence in an intensive care unit (ICU), serum creatinine, and donor age. Additional regression analysis revealed that the increase in mortality risk associated with HCV was concentrated between 3 and 24 months postretransplantation, among patients age 18 to 39 at retransplant, and in patients retransplanted during the years 2000 to 2002. In conclusion, HCV liver recipients account for a considerable proportion of all retransplantations performed. Surprisingly, younger age predicted a higher mortality for recipients with HCV undergoing liver retransplantation. This may reflect a willingness to retransplant younger patients with an increased severity of illness or a more virulent HCV infection in this population. Although HCV was predictive of an increased risk of death, consideration of other characteristics of HCV patients, including donor and recipient age and need for preoperative ICU care may identify those at significantly higher risk.