Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial.

BACKGROUND: The use of alemtuzumab as induction immunosuppression for renal transplantation introduces the possibility of long-term tacrolimus monotherapy, avoiding maintenance with both corticosteroids and mycophenolate mofetil (MMF). METHODS: We conducted a single-center, prospective, open-label, randomized controlled trial comparing two steroid avoidance regimens between December 2006 and November 2010. One hundred and sixteen adult patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or to alemtuzumab induction followed by tacrolimus monotherapy. The primary endpoint was noninferiority of isotopic glomerular filtration rate at 1 year; secondary endpoints included patient and graft survival, incidence of delayed graft function, and incidence and severity of biopsy-proven acute rejection. RESULTS: The two groups were well matched for all baseline demographics. Isotopic glomerular filtration rate was comparable between the groups at 1 year (57±26 mL/min for alemtuzumab group and 53±21 mL/min for basiliximab group; P=0.42). Secondary endpoints were also similar between the groups. The rate of biopsy-proven acute rejection by 12 months was lower in the alemtuzumab group (n=6 vs. n=14 in basiliximab arm) just reaching statistical significance (P=0.049); however, a single extra case in the alemtuzumab arm included when considering clinically treated rejection removes this significance (P=0.082). Similar rates of cardiovascular, infective, and neoplastic complications were observed in both groups. Forty-seven (81.0%) of the patients in the alemtuzumab group remained on tacrolimus monotherapy at 12 months. CONCLUSIONS: Renal transplantation with alemtuzumab induction followed by tacrolimus monotherapy leads to good graft and patient outcomes, with no major differences detected compared with basiliximab induction and tacrolimus/MMF maintenance at 1 year.

Increased morbidity in overweight and obese liver transplant recipients: a single-center experience of 1325 patients from the United Kingdom.

Obesity levels in the United Kingdom have risen over the years. Studies from the United States and elsewhere have reported variable outcomes for obese liver transplant recipients in terms of post-liver transplant morbidity, mortality, and graft survival. This study was designed to analyze the impact of the body mass index (BMI) on outcomes following adult liver transplantation. Data from 1994 to 2009 were retrieved from a prospectively maintained database. Patients were stratified into 5 World Health Organization BMI categories: underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)), obese (30.0-34.9 kg/m(2)), and morbidly obese (≥35.0 kg/m(2)). The primary outcome was an evaluation of graft and patient survival, and the secondary outcome was an assessment of postoperative morbidity. Bonferroni correction was applied with statistical significance set at P < 0.012. Kaplan-Meier curves were used to study the effects of BMI on graft and patient survival. A total of 1325 patients were included in the study: underweight (n = 47 or 3.5%), normal-weight (n = 643 or 48.5%), overweight (n = 417 or 31.5%), obese (n = 145 or 10.9%), and morbidly obese patients (n = 73 or 5.5%). The rate of postoperative infective complications was significantly higher in the overweight (60.7%, P < 0.01) and obese recipients (65.5%, P < 0.01) versus the normal-weight recipients (50.4%). The morbidly obese patients had a longer mean intensive care unit (ICU) stay than the normal-weight patients (4.7 versus 3.2 days, P = 0.03). The mean hospital stay was longer for the overweight (22.4 days, P < 0.001), obese (21.3 days, P = 0.04), and morbidly obese recipients (22.4 days, P = 0.047) versus the normal-weight recipients (18.0 days). There was no difference in death-censored graft survival or patient survival between the groups. In conclusion, this is the largest and only reported UK series on BMI and outcomes following liver transplantation. Overweight and obese patients have significantly increased morbidity in terms of infective complications after liver transplantation and, consequently, longer ICU and hospital stays.

Rectal epithelial cell mitosis and expression of macrophage migration inhibitory factor are increased 3 years after Roux-en-Y gastric bypass (RYGB) for morbid obesity: implications for long-term neoplastic risk following RYGB.

BACKGROUND: Rectal epithelial cell mitosis and crypt size, as well as expression of proinflammatory genes including macrophage migration inhibitory factor (MIF), are increased 6 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients. Tests were carried out to determine whether these putative colorectal cancer risk biomarkers remained elevated long term after RYGB, and the mechanistic basis, as well as the functional consequences, of Mif upregulation in intestinal epithelial cells was investigated. METHODS: Rectal mucosa and blood were obtained a median of 3 years after RYGB from the original cohort of patients with RYGB (n = 19) for crypt microdissection, real-time PCR, immunohistochemistry for MIF and immunoassay of proinflammatory markers. Immunohistochemistry for Mif and bromodeoxyuridine labelling were performed on AhCre⁺ mouse and Apc(Min/⁺) mouse (with and without functional Mif alleles) intestine, respectively. RESULTS: Rectal epithelial cell mitosis and crypt size remained elevated 3 years after RYGB compared with preoperative values (1.7- and 1.5-fold, respectively; p < 0.05). There was a 40-fold (95% CI 13 to 125) increase in mucosal MIF transcript levels at 3 years associated with increased epithelial cell MIF protein levels. Conditional Apc loss in AhCre⁺ mice led to increased epithelial cell Mif content. Mif deficiency in Apc(Min/⁺) mice was associated with a combined defect in intestinal epithelial cell proliferation and migration, which was reflected by the longitudinal clinical data. CONCLUSIONS: Mucosal abnormalities persist 3 years after RYGB and include elevation of the protumorigenic cytokine MIF, which is upregulated following Apc loss and which contributes to intestinal epithelial cell homeostasis. These observations should prompt clinical studies of colorectal neoplastic risk after RYGB.

Liver transplantation following donation after cardiac death: an analysis using matched pairs.

Grafts from donation after cardiac death (DCD) donors are used to increase the number of organs available for liver transplantation. There is concern that warm ischemia may impair graft function. We compared our DCD recipients with a case-matched group of donation after brain death (DBD) recipients. Between January 2002 and April 2008, 39 DCD grafts were transplanted. These were matched with 39 DBD recipients on the basis of identified variables that had a significant impact on mortality. These were used to individually match DCD and DBD patients with similar predictive mortality. We compared patient/graft survival, primary non-function (PNF), and rates of complications. Of all liver transplants, 6.1% were DCD grafts. PNF occurred twice in the DCD group. The incidence of nonanastomotic biliary strictures (NABS; 20.5% versus 0%, P = 0.005) and hepatic artery stenosis (HAS; 12.8% versus 0%, P = 0.027) in the DCD group was higher. One-year (79.5% versus 97.4%, P = 0.029) and 3-year (63.6% versus 97.4%, P = 0.001) graft survival was lower in the DCD group. Three-year patient survival was also lower (68.2% versus 100%, P < 0.0001). Our study is the first to use case-matched patients and compare groups with similar predictive mortality. There was a higher incidence of NABS and HAS in the DCD group. NABS were likely a result of warm ischemia. HAS may have been due to ischemia or arterial injury during retrieval. The DCD group had significantly poorer outcomes, but DCD grafts remain a valuable resource. With careful donor/recipient selection, minimization of ischemia, and good postoperative care, acceptable results can be achieved.

Donor risk index and MELD interactions in predicting long-term graft survival: a single-centre experience.

INTRODUCTION: Feng et al. described the donor risk index (DRI) in North American liver transplant recipients. We evaluated the effect of the DRI and model for end-stage liver disease (MELD) score on liver transplant recipients from a single center in the United Kingdom. METHOD: Prospectively, collected data of all patients transplanted at our center between January 1995 and December 2005 were included in the analysis (n=1090). Outcomes evaluated included patient-censored and death-censored graft survival. Outcomes of liver transplantation from "high" and "low" DRI groups (> or =1.8 and <1.8, respectively) on patients categorized into low (<15), intermediate (15-30), and high (>30) MELD categories were analyzed. RESULTS: MELD at transplant was the only significant predictor of patient survival. MELD at transplant and DRI more than 1.7 were associated with a poorer graft survival (P=0.03). There was a trend toward poorer graft survival in high DRI grafts transplanted in low and "intermediate" MELD categories (P=0.47 and 0.006, respectively). However, in the high MELD category, there was a similar graft survival for both high and low DRI grafts. CONCLUSION: Patients with low and intermediate MELDs at transplantation may be better served by a low DRI graft, whereas patients with high MELD may not be compromised by receiving a high DRI graft.

Outcomes in right liver lobe transplantation: a matched pair analysis.

Split liver transplantation (SLT) has proven to be an effective technique of increasing the donor pool and thereby reducing adult and paediatric waiting list mortality. There remains concern regarding complications in adult recipients. Here, we compare SLT with matched whole liver grafts. Adult recipients of primary extended right lobe grafts (ERL) were matched to recipients of whole liver transplantations (WLTs) according to the following criteria: model of end-stage liver disease (MELD) score, recipient age, indication for liver transplantation and year of transplantation. Twenty-seven pairs of recipients were transplanted for chronic liver disease. The overall 30-day patient survival rates after ERL and WLT were 88.9% and 92.5% and 3-year survival rates after SLT and WLT were 77.8% and 85.2% respectively (log-rank = 0.38). Two patients with SLTs had hepatic artery thromboses and were retransplanted with none from the WLT group. The prevalence of a biliary leak was higher among the SLT group (n = 4) compared with none in the WLT group (P = 0.05). Patients with preoperative hyponatraemia showed a trend towards poorer survival after SLT compared with WLT. Our data suggest that SLT with extended right liver lobes, although not significantly different, shows a trend towards a poorer outcome.

Increased colorectal epithelial cell proliferation and crypt fission associated with obesity and roux-en-Y gastric bypass.

BACKGROUND AND AIMS: The relationship between obesity, weight reduction, and future risk of colorectal cancer is not well understood. Therefore, we compared mucosal biomarkers in normal weight individuals [body mass index (BMI), 18.5-24.9 kg/m(2)] with those in morbidly obese patients (BMI >40 kg/m(2)) before and 6 months after Roux-en-Y gastric bypass (RYGB). METHODS: Rectal epithelial cell mitosis, crypt area, and crypt branching were measured following whole crypt microdissection. Apoptosis was measured by immunohistochemistry for neo-cytokeratin 18 on fixed tissue sections. Serum levels of C-reactive protein and cytokines were assayed in combination with quantification of mucosal proinflammatory gene expression by real-time RT-PCR. RESULTS: Twenty-six morbidly obese patients (mean BMI, 54.4 kg/m(2)) had significantly increased mitosis, crypt area, and crypt branching (all P < 0.01) compared with 21 age- and sex-matched normal weight individuals (mean BMI, 22.5 kg/m(2)). Morbidly obese patients underwent a mean excess weight loss of 41.7% at a mean of 26 weeks after RYGB. Surprisingly, this was associated with a further increase in mitosis and decreased apoptosis of epithelial cells. At the same time, lower levels of serum C-reactive protein and interleukin-6 following RYGB were accompanied by a reduction in mucosal IL-6 protein content but elevated mucosal expression of other proinflammatory genes such as cyclooxygenase-1 and cyclooxygenase-2. CONCLUSIONS: Mucosal biomarkers, accepted as indicators of future colorectal cancer risk, are increased in morbidly obese patients compared with normal weight controls. The hyperproliferative state that exists 6 months after RYGB may have important implications for long-term colorectal cancer risk in bariatric surgery patients.

Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation.

Vascular disease and chronic allograft nephropathy have prompted re-evaluation of steroids and calcineurin inhibitors (CNIs) in renal transplantation. Sirolimus (SRL) can facilitate early CNI withdrawal. We report on the Early CNI and Steroid Elimination in Leeds (ECSEL) study, which was terminated early due to poor tolerability of SRL. Basiliximab/methylprednisolone induction was used, then 2 months of tacrolimus (TAC) and mycophenolate mofetil (MMF) treatment. A total of 51 patients were randomized to continue TAC/MMF or switch to SRL/MMF. In ECSEL1, patients were switched at 2 months (n=10). In ECSEL2, SRL was introduced at months 4-6 and TAC was tapered (n=13). Median overall follow up was 701 days. All 10 ECSEL1 and 10 of 13 (77%) ECSEL2 patients discontinued SRL due to adverse events, including leucopenia, rash, mucosal ulceration, arthralgia, and possible pneumonitis. Mean end-of-study creatinine was comparable in all groups. Sirolimus should be used with caution in complete CNI and steroid withdrawal, due to the resultant intolerable adverse event profile.

Emergency subtotal hepatectomy: a new concept for acetaminophen-induced acute liver failure: temporary hepatic support by auxiliary orthotopic liver transplantation enables long-term success.

INTRODUCTION: Acetaminophen (paracetamol) overdose (AOD) has recently emerged as the leading cause of acute liver failure (ALF) in the United States, with an incidence approaching that seen in the United Kingdom. We describe a new way to treat AOD ALF patients fulfilling King's College criteria for "super-urgent" liver transplantation. METHODS: Beginning in June 1998, we have been piloting a clinical program of subtotal hepatectomy and auxiliary orthotopic liver transplantation (ALT) for AOD ALF. Our technique is based on the following principles: (1) subtotal hepatectomy; (2) auxiliary transplantation of a whole liver graft; (3) gradual withdrawal of immunosuppression after recovery. Results were compared with patients who had undergone an orthotopic liver transplantation (OLT) for AOD ALF in the same period. Quality of life comparisons were made using the SF36 questionnaire. RESULTS: Thirteen patients underwent this procedure between June 1998 and March 2005. Median survival is 68 months (range, 0-102 m). Actual survival data show that 9 of 13 patients are alive (69%) compared with 7 of 13 OLT patients (54%). One ALT patient required a retransplantation with an OLT due to hepatic vein thrombosis, and immunosuppression is therefore maintained. The other 8 surviving ALT patients are off immunosuppression. These 8 ALT patients have normal liver function and have a better quality of life compared with the 7 surviving OLT patients. CONCLUSION: Our results with this new technique are encouraging: 69% actual survival, no long-term immunosuppression requirement, and improved quality of life in the 62% successful cases.

The value of MELD and sodium in assessing potential liver transplant recipients in the United Kingdom.

As the result of the widening gap between supply and demand of organs for liver transplantation, efforts to improve allocation have become an increasingly important yet controversial subject. The MELD score has been adopted in the USA but its usefulness has rarely been examined in Europe. We carried out an intention to treat analysis of 422 patients placed on our transplant waiting list over a 5-year period. We examined multiple variables to investigate the value of MELD, sodium and other factors in predicting post-transplant outcomes. MELD at transplant was the most important indicator of post-transplant outcomes. In addition, delta-MELD and hyponatreamia were significant at predicting, which patients placed on the waiting list would not proceed to transplant. While a move to allocating solely by MELD is not justified in the UK allocation system, there is value in using MELD, delta-MELD and hyponatreamia in making decisions regarding the allocation of organs. This may subsequently help to improve overall outcomes.

Endovascular management of arterial conduit pseudoaneurysm after liver transplantation: a report of two cases.

We describe two cases of pseudoaneurysms in liver-transplant iliac artery conduits, which were successfully treated with endovascular stent grafting.

Vascular access survival in children and young adults receiving long-term hemodialysis.

BACKGROUND: The delivery of long-term hemodialysis therapy in children is complicated by smaller vascular caliber and the potential lifelong requirement for hemodialysis access. Various factors have resulted in the increased use of cuffed central venous catheters (CVLs) in preference to autologous arteriovenous fistulae (AVFs) and arteriovenous synthetic grafts (AVGs). The aim of this study is to compare CVL, AVF, and AVG survival and determine factors affecting their survival. METHODS: A 20-year retrospective study was undertaken of pediatric patients receiving long-term hemodialysis therapy. Age, height, weight, body mass index, and sex were noted at each procedure, in addition to the presence of hypoalbuminemia, underlying diagnosis, type and site of vascular access, and effect of previous access surgery. The grade of operator also was noted. RESULTS: Three hundred four vascular access procedures were performed on 114 patients, with a median age at initial access formation of 12.0 years (range, 4 weeks to 21.9 years). The most common procedure was CVL insertion (182 procedures) and then AVF formation (107 procedures), with only 15 AVGs created. Median censored survival was 3.14 years (95% confidence interval, 1.22 to 5.06) for AVFs and 0.6 years (95% confidence interval, 0.20 to 1.00) for CVLs. Factors adversely affecting vascular access survival were younger age, trainee operator, presence of hypoalbuminemia, and type of access undertaken, with AVF better than CVL. CONCLUSION: This study shows increased survival of AVFs over CVLs and AVGs. Vascular access in children and adolescents may impact on future dialysis accessibility and should be undertaken by those most experienced in each technique.

Bile duct strictures after hepatobiliary surgery: assessment with MR cholangiography.

PURPOSE: To establish the accuracy of magnetic resonance (MR) cholangiography for diagnosis of postsurgical bile duct strictures. MATERIALS AND METHODS: Sixty-seven patients suspected of having bile duct strictures after liver transplantation (n = 54), cholecystectomy (n = 8), hepatic resection (n = 4), or pancreaticoduodenectomy (n = 1) underwent MR cholangiography. Thick-slab single-shot fast spin-echo (repetition time msec/echo time msec, 4,500/940) imaging was performed in the coronal through sagittal planes with rotation in 10 degrees increments, and contiguous thin-section images were obtained in the transverse and the optimal coronal oblique planes by using half-Fourier rapid acquisition with relaxation enhancement (1,900/96). Three blinded observers independently reviewed the MR images and recorded diagnostic features including presence of biliary stricture by using a five-point confidence scale. Receiver operating characteristic analysis was used to measure the accuracy of MR cholangiography. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Final diagnosis was established at surgery (n = 29) and direct cholangiography (23 of 29) or at direct cholangiography, liver biopsy, and/or serial liver function tests (n = 38). RESULTS: Thirty-three of 67 patients had strictures confirmed with the reference standard. MR cholangiography enabled correct diagnosis and depicted the site of strictures in all cases. Findings of stricture at MR cholangiography were false-positive in five patients with moderate duct dilatation and caliber change at the level of the anastomosis. Mean accuracy, sensitivity, specificity, PPV, and NPV were 94%, 97%, 74%, 86%, and 96%, respectively. CONCLUSION: MR cholangiography is as sensitive as direct cholangiography for the assessment of bile duct strictures after hepatobiliary surgery but may lead to overestimation of the importance of duct dilatation and caliber change.

Surgical strategy for cystic diseases of the liver in a western hepatobiliary center.

The aim of this study was to define the indications and evaluate the results of various management options in patients with cystic liver disease. Between 1992 and 1999 we managed 60 consecutive patients with cystic liver disease. Diagnoses included a simple cyst (solitary 12, multiple 10), adult polycystic liver disease (APLD 17), Caroli's disease (8), hydatid cysts (4), and neoplastic cysts (9). Half of the patients with simple cysts had mild or no symptoms and required no treatment. Percutaneous drainage in eight patients (simple cyst 4, APLD 4) was followed by symptomatic recurrence in three. Laparoscopic deroofing in three patients (multiple simple cysts 2, APLD 1) was followed by symptomatic enlargement of the remaining cysts that required further intervention (laparoscopic deroofing 2, transplantation 1). Laparoscopic hepatectomy was successful in three patients with solitary simple cysts. Of 18 patients who underwent open hepatic resection (neoplastic 8, Caroli's 4, simple cysts 3, hydatid cysts 2, APLD 1), 2 patients with Caroli's disease required liver transplantation for disease progression. Nine patients (Caroli's 5, APLD 4) underwent liver transplantation, and three had a concomitant renal transplant. Seven patients developed complications, and three died (5%). Cholangiocarcinoma developed in three patients with bilateral Caroli's disease, and all died. Radiologic treatment has a limited role in the management of patients with simple cysts or APLD. Laparoscopic deroofing of simple cysts may have to be repeated, whereas resection minimizes cyst recurrence. Unilobar Caroli's disease may be resected, whereas bilateral disease requires early liver transplantation owing to the high risk of malignancy. Transplantation is a reserved option in patients with extensive APLD.