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.

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.

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.

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.

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.

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.

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.

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.

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.

Renal transplantations performed using non-heart-beating organ donors: going back to the future?

BACKGROUND: As more expanded-criteria organ donors are used to bridge the widening gap between organ supply and demand, non-heart-beating (NHB) donors will become increasingly important. The purpose of this study was to analyze renal transplant outcomes using this source of cadaveric (CAD) organs and compare the results with heart-beating organ sources. METHODS: Data from 98,698 adult CAD renal transplant recipients and 34,531 living donor renal transplant recipients registered in the U. S. Renal Data System database between January 1993 and June 2000 were analyzed. Kaplan-Meier survival curves were used to compare graft and patient survival rates between NHB, CAD, and living donor transplant recipients. Cox proportional hazards models were used to identify risk factors for NHB donor recipients, while adjusting for potential confounding variables. RESULTS: Recipients of NHB donor organs experienced nearly twice the incidence of delayed graft function (DGF) compared with heart-beating donors (42.4% vs. 23.3%, respectively). NHB donor transplants experienced comparable allograft survival when compared with CAD transplants at 6 years (73.2% vs. 72.5%, respectively; P=NS); patient survival was greater at 6 years for NHB compared with CAD renal transplant recipients (80.9% vs. 77.8%, respectively; P=NS). Significant factors for allograft loss for NHB donor organ recipients included the following: organ used for repeat transplants; DGF; donor age older than 35 years; and head trauma as a cause of initial injury (relative risk 2.74, 1.90, 1.78, and 1.41, respectively). CONCLUSIONS: Although exhibiting elevated DGF rates, allograft and patient survival rates of transplants from NHB donor sources are equivalent to those from conventional CAD sources. Donor age, recipient transplant number, female recipient, mechanism of injury, and DGF were the most pertinent variables leading to poor outcomes.

Epithelioid hemangioendothelioma of the liver disseminated to the peritoneum treated with liver transplantation and interferon alpha-2B.

Epithelioid hemangioendothelioma (EH) is a rare, low-grade, malignant neoplasm of vascular origin that may develop at different sites, such as in the soft tissue, lungs, or liver. We report the case of a 21-year-old female with primary EH of the liver treated by liver transplantation and review the available literature on EH. This patient developed symptomatic recurrence of the tumor in the pelvis 2 months posttransplant. Treatment with interferon alpha-2b resulted in substantial regression of the pelvic metastases and alleviation of symptoms, but the patient developed graft rejection and died of associated complications 16 months posttransplant. This report is the first showing the efficacy of interferon in this setting.

Long-term follow-up of percutaneous transhepatic balloon cholangioplasty in the management of biliary strictures after liver transplantation.

BACKGROUND: This study evaluated the efficacy of a protocol of initial balloon dilation for biliary strictures after liver transplantation. METHODS: Complete records from 96 patients with biliary strictures were retrospectively reviewed. Seventy-six patients received percutaneous transhepatic balloon cholangioplasty (PTBC) after initial placement of biliary drainage (percutaneous transluminal cholangiography [PTC]) tube. In most cases, three dilations were performed with a 4 to 8 week interval between procedures. Follow-up ranged from 6 months to 10 years. RESULTS: PTBC successfully treated strictures in 39 of 76 (51.3%) cases. Factors favoring successful PTBC included older age at transplant, shorter cold ischemic time, and single strictures. There were nine recurrent strictures after PTBC, all of which were successfully treated by nonoperative measures. The number of dilations performed affected both the likelihood of success and the long-term risk of stricture recurrence. Of the 37 PTBC failures, 14 underwent subsequent surgical revision. When both angiographic and surgical modalities were considered, treatment success was associated with first transplants, shorter cold ischemic time and operative time, and less intraoperative transfusion requirements. Factors associated with treatment failure included multiple, central hepatic duct, and intrahepatic strictures. PTC-tube independence was achieved in 51 of 76 (67%) patients using the combined approach of PTBC and surgery for PTBC failures. CONCLUSIONS: PTBC is an effective initial modality for treating posttransplant biliary strictures. Prolonged cold ischemic and operative times and multiple or peripheral strictures predispose to treatment failure. Solitary extrahepatic strictures that fail PTBC are salvageable with surgical revision with excellent results.

Evaluation of pancreatic allograft dysfunction by laparoscopic biopsy.

BACKGROUND: Histologic evaluation of a failing pancreatic allograft is necessary for accurate classification of graft dysfunction. Unlike percutaneous or transcystoscopic techniques, laparoscopic biopsy allows visualization of the allograft in addition to obtaining tissue for histologic examination. METHODS: We retrospectively reviewed all laparoscopic pancreas transplant biopsies performed over a 15-month period ending February 2002. RESULTS: There were 12 laparoscopic pancreas biopsies performed in 11 patients between 6 weeks and 8 years (mean 2.5+/-2.8 years) after transplant. Indications for biopsy were hyperglycemia (n=8), hyperamylasemia (n=3), and graft tenderness (n=1). Adequate tissue was obtained in 11 of 12 biopsies. Two patients received definitive treatment at the time of laparoscopy (pseudocyst debridement, ovarian cyst excision). CONCLUSIONS: Laparoscopic pancreas transplant biopsy allows safe visualization of the allograft and effective specimen retrieval, and in some cases provides the opportunity for therapeutic intervention.

Gender imbalance in living donor renal transplantation.

BACKGROUND: Previous studies have shown more women than men among living donors (LD) and more men among recipients of those kidneys. In this study, we compared the evolving demographics of LD transplants. METHODS: We retrospectively analyzed all LD transplants performed in our center between 1964 and 2000. RESULTS: Among 1182 LD cases, 1035 (88%) were biologically related (LRD) and 147 (12%) were unrelated (LURD). LURD donors and recipients were significantly older than LRD donors and recipients, respectively (P=0.0001). More LURD allograft recipients were male (71%) compared with LRD recipients (57%) (P=0.0013). The proportion of female donors was 55% in both groups. Spousal donations were predominantly wife-to-husband (69%). Compared with the LRD group, there was a greater proportion of female-to-male LURD transplants (46 vs. 30%) and a smaller proportion of female-to-female LURD transplants (10 vs. 25%) (P=0.0001). When spousal pairs were excluded from the analysis, there was a higher proportion of male-to-male (48 vs. 27%) donations and a lower proportion of male-to-female (18 vs. 9%) and female-to-female (25 vs. 17%) transplants in the LURD group (P=0.001). CONCLUSIONS: Gender disparities in LD transplantation are primarily due to a higher proportion of wife-to-husband donations and a lower incidence of male-to-female grafts among nonspousal LURD transplants. Strategies should be devised to ensure access for women to renal transplantation and to encourage and facilitate donation by men.

Prospective, randomized trial of the effect of antibody induction in simultaneous pancreas and kidney transplantation: three-year results.

BACKGROUND: Historically, antibody induction has been used because of the higher immunologic risk of graft loss or rejection observed in simultaneous pancreas and kidney (SPK) transplantation compared with kidney transplantation alone. This trial was designed to assess the effect of antibody induction in SPK transplant recipients receiving tacrolimus, mycophenolate mofetil, and corticosteroids. Induction agents included T-cell-depleting and interleukin-2 receptor antibodies. METHODS: A total of 174 SPK transplant recipients were enrolled in a prospective, open-label, multi-center study. They were randomized to induction (n=87) or non-induction (n=87) groups and followed for 3 years. RESULTS: At 3 years, actual patient (94.3% and 89.7%) and pancreas (75.9% and 75.9%) survivals were similar between the induction and non-induction groups, respectively. Actual kidney survival was similar at 1 and 2 years, but at 3 years, it was significantly better in the induction group compared with the non-induction group (92% vs. 81.6%; P =0.04). At 3 years, median serum creatinine and hemoglobin A1C were similar between the induction and non-induction groups (1.35 mg/dL and 1.20 mg/dL, 5.4% and 5.5%, respectively). Three-year cumulative incidence of biopsy-confirmed, treated acute kidney rejection in the induction and non-induction groups was 19.5% and 27.5% (P =0.14), respectively, with odds 4.6 times greater in African Americans regardless of treatment (P =0.004). Significantly higher rates of cytomegalovirus (CMV) viremia and CMV syndrome occurred in those receiving T-cell-depleting antibody induction (36.1%) when compared with those receiving anti-interleukin-2 receptor antibodies (2%) and non-induction (8.1%) (P <0.0001). CONCLUSIONS: Tacrolimus, mycophenolate mofetil, and corticosteroids resulted in excellent safety and efficacy in SPK transplant recipients. Actual 3-year kidney survival was significantly better in the induction group; however, CMV viremia and CMV syndrome rates were significantly higher in the T-cell-depleting antibody group. African Americans demonstrated a significantly greater risk of acute rejection despite antibody induction. Decisions regarding the use of induction therapy must weigh the risk of kidney graft loss or rejection against the risk of infection.

Kidney transplantation from organ donors following cardiopulmonary death using extracorporeal membrane oxygenation support.

Extracorporeal membrane oxygenation (ECMO) has the ability to provide normal organ perfusion and oxygenation in the absence of cardiac function and thus has the potential to improve viability of subsequently transplanted kidneys. In addition, ECMO support allows the donation following cardiopulmonary death (DCD) process to occur in a controlled manner that is acceptable to staff unfamiliar with DCD. In 1999 our center implemented a controlled DCD program that incorporates post-mortem ECMO support of the organs. Arterial and venous cannulae are placed following consent to donate, but prior to withdrawal of support. ECMO circulation is initiated immediately following declaration of death. Following a brief period where the donor family is allowed to grieve, the donor is moved to the operating room where organ recovery occurs. We reviewed the results of 20 kidney transplants from 13 ECMO supported donors that occurred between October 2000 and August 2003. One renal allograft was lost due to surgical complications, all 19 remaining grafts functioned. An 11% (2/19) delayed graft function rate was observed. Kidneys donated from "controlled" ECMO supported CPD donors are a viable source of organs for renal transplantation. This recovery method warrants further investigation.

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.