Steven I. Hanish

Safety of belatacept bridging immunosuppression in hepatitis C-positive liver transplant recipients with renal dysfunction.

Background Perioperative renal dysfunction in liver transplant recipients complicates maintenance immunosuppressive therapy, particularly in patients with hepatitis C. Calcineurin inhibitors exacerbate renal dysfunction and mammalian target-of-rapamycin inhibitors are generally avoided because of perceived perioperative risks. The authors’ experience with seven liver transplant patients who received belatacept and mycophenolic acid maintenance immunosuppression is reported. Methods A retrospective review of adult liver transplant recipients with hepatitis C receiving belatacept was conducted under Institutional Review Board approval. All patients were Epstein-Barr virus IgG seropositive. The primary endpoint was patient and graft survival, with secondary endpoints including the incidence of acute rejection, degree of renal function recovery, and occurrence of major side effects. Results Between December 19, 2011 and January 25, 2013, seven liver transplant recipients with hepatitis C received belatacept immunosuppression in the perioperative period. The primary indication for belatacept was perioperative renal dysfunction. Belatacept was initiated between 2 and 90 days posttransplant and the duration of belatacept therapy ranged from 19 to 89 days. Patients were transitioned onto calcineurin inhibitor therapy when they reached chronic kidney disease stage 2 or better. Six-month patient and graft survival was 86%. There was one episode of graft rejection on belatacept therapy in a patient who had also had early rejection before initiation of belatacept. Conclusions The results in this initial group of patients suggest that belatacept with mycophenolic acid may be a safe maintenance immunosuppression regimen in hepatitis C–positive liver transplant recipients with renal dysfunction, and that this regimen can serve as an effective bridge to calcineurin inhibitor therapy.

Intraoperative Continuous Veno-Venous Hemofiltration Facilitates Surgery in Liver Transplant Patients With Acute Renal Failure

INTRODUCTION We have aggressively used continuous veno-venous hemofiltration (CVVH) on high model for end-stage liver disease (MELD) score liver transplant patients with acute kidney injury and hypothesized that the addition of intraoperative CVVH therapy would improve overall outcomes. METHODS We performed a retrospective review of all adult, single organ, liver transplant recipients requiring preoperative renal replacement therapy between January 1, 2011 and June 1, 2013. Intraoperative and perioperative records and laboratory values were collected and used to create a database of these patients. Patients were grouped according to whether or not they underwent CVVH at the time of liver transplantation. RESULTS Twenty-one patients with new-onset renal failure requiring preoperative renal replacement therapy received a liver transplant alone. Fourteen received intraoperative CVVH and 7 patients did not. The average MELD score was similar between groups (34 for intraoperative CVVH vs 35; P = .8). Preoperative sodium and potassium were higher for the group receiving intraoperative CVVH, but still fell within normal ranges. Preoperative lactate levels were higher in the group that received intraoperative CVVH (4.7 vs 2.0 mmol/L; P = .01). Intraoperative CVVH did not decrease intraoperative transfusion requirements or intensive care unit (ICU) and hospital lengths of stay. Differences in reoperative rates did not reach statistical significance. All patients were weaned off renal replacement therapy. One-year patient survival rate was 86% for intraoperative CVVH versus 71% without. CONCLUSION The judicious use of intraoperative CVVH therapy may permit patients with increasing severity of illness to achieve outcomes comparable with less ill patients.

Molecular Adsorbent Recirculating System Effectively Replaces Hepatic Function in Severe Acute Liver Failure

Summary Background Data: Patients with severe acute liver failure (ALF) have extreme physiologic dysfunction and often die if transplantation is not immediately available. Patients may be supported with MARS (Baxter International Inc., Deerfield, IL) until transplantation or spontaneous recovery occurs. We present the largest series in the United States of MARS therapy as temporary hepatic replacement for ALF. Methods: MARS was used to support patients with severe liver trauma (SLT), in ALF patients as a bridge to transplantation (BTT), and as definitive therapy for toxic ingestion or idiopathic liver failure (DT) in a level 1 trauma center and large transplant center. Patient demographics, etiology of ALF, and laboratory values were recorded. Endpoints were patient survival ± liver transplant and/or recovery of liver function. Results: Twenty-seven patients with severe ALF received MARS therapy. Five patients with SLT had a 60% survival with recovery of liver and renal function. Thirteen patients received MARS as a BTT, of which 9 were transplanted with a 1-year survival of 78% (program overall survival 85% at 1 year). All 4 who were not transplanted expired. Nine patients with ALF from toxic ingestion received MARS as DT with liver recovery and survival in 67%. MARS therapy resulted in significant improvement in liver function, coagulation, incidence of encephalopathy, and creatinine. Conclusions: MARS therapy successfully replaced hepatic function in ALF allowing time for spontaneous recovery or transplantation. Spontaneous recovery was remarkably common if support can be sustained.

Resolution of Donor Non-Alcoholic Fatty Liver Disease Following Liver Transplantation

Transplant surgeons conventionally select against livers displaying high degrees (>30%) of macrosteatosis (MaS), out of concern for primary non‐function or severe graft dysfunction. As such, there is relatively limited experience with such livers, and the natural history remains incompletely characterized. We present our experience of transplanted livers with high degrees of MaS and microsteatosis (MiS), with a focus on the histopathologic and clinical outcomes.

Sequential kidney–liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency

Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end‐stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency.

Liver transplantation in patients with multiple organ failures: Feasibility and outcomes

BACKGROUND & AIMS Multiple organ failures (OFs) are common in patients with cirrhosis, but the independent effect of the number or type of OFs on liver transplantation (LT) outcomes is not well defined. METHOD United Network for Organ Sharing data were analyzed from 2002 to 2016 for all adults listed for LT who received an LT within 30 days after listing. We estimated post-LT survival stratified by number and type of pre-transplant OFs before and after adjusting for confounding variables. RESULTS During the study period, 4,714 (4.1%) patients died and 19,375 (16.6%) patients were transplanted within 30 days of listing. One or more OF were more common in those who were transplanted (57.4%) compared to those without LT (9.5%). The probability of staying alive more than 30 days on the waiting list without LT decreased with increasing number of OFs; while 90% were alive without OF, only 20% were alive with two OFs, and 2-8% with three or more OFs. The interval between listing and transplantation decreased with an increase in OFs, and the median time to transplant after listing was only 4-5 days with three or more OFs. Although the risk of post-LT mortality increased with increasing number of OFs, the 90-day patient survival was 90% and one-year survival was 81% in the presence of 5-6 OFs. The number of OFs was an independent predictor of survival, but the maximum difference in one-year graft or patient survival between those without OF and those with 5-6 OFs was only 9%. Additionally, the type of OF had minimal impact on outcomes. CONCLUSIONS Liver transplantation is feasible with excellent outcomes, even in the presence of five or six OFs. LAY SUMMARY Multiple organ failures, ranging from 1-6, are common in hospitalized patients with cirrhosis. The survival without liver transplant is dismal in the presence of three or more organ failures. Small retrospective studies have shown that liver transplant is feasible with good outcomes even in the presence of multiple organ failures. In this study, using a large national dataset, we show that survival chances for more than 30 days in those with three or more organ failures are less than 8%. However, if a liver transplant is performed quickly, the survival chances are very high with one-year survival ranging from 84% with three organ failures to 81% with 5-6 organ failures.

Recurrence of Hepatocellular Carcinoma Following Liver Transplantation Within Milan Criteria

The optimal curative options for the management of hepatocellular carcinoma (HCC) are surgical resection and/or liver transplantation (LT). Recent data suggest that ablative treatment such as radio frequency ablation (RFA) may be comparable to surgical resection for small tumors. The 5-year tumor-free survival after surgical resection (or RFA) is less than LT irrespective of the risk factor for HCC. LT is considered the best option in people with HCC and portal hypertension, or those with advanced cirrhosis because of lower surgical mortality rates. Prior to the introduction of Milan criteria, the long-term results of liver transplantation in patients with hepatocellular carcinoma have been variable and disappointing, with an overall 5-year survival rate ranging from 30 to 40 %. Application of Milan criteria has reduced tumor recurrence rates to ~10 % and has improved 5-year tumor-free survival (~70 %). The UNOS data also suggested that the survival improved after the publication of Milan criteria in the United States. There is an ongoing debate whether Milan criteria could be expanded without having an adverse effect on tumor-free survival. Published studies suggest that HCC patients transplanted outside the Milan criteria have 5-year survival rates between 46 and 60 %. One of the major criticisms of Milan criteria is that it is based on pre-LT imaging findings, and only 70 % of explant pathology findings correlate with imaging. Moreover, imaging techniques, protocols, and interpretations of images are not uniform, and additionally, Milan criteria do not take into consideration the variability of tumor biology. As we understand the variability of HCC tumor biology better and develop reliable molecular markers, we may be able to redefine the LT selection criteria for patients with HCC without any negative effects of outcomes. Until then, Milan criteria appear to be a reasonable benchmark for selecting HCC patients for LT.

Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child–Turcotte–Pugh Class C Cirrhosis and Renal Dysfunction

Phosphodiesterase-5 (PDE-5) inhibitors have been used successfully in patients with cirrhosis to treat porto-pulmonary hypertension. Additionally, in cirrhosis, PDE-5 inhibitors can potentially improve portal hypertension and renal hemodynamics. No pharmacokinetics and tolerability studies of intravenous (IV) sildenafil have been conducted in Child-Turcotte-Pugh (CTP) class C cirrhosis and renal dysfunction. We report two subjects with CTP class C cirrhosis and estimated glomerular filtration rate of 25.8 and 22.4 ml/min/1.73m2 treated with a single-dose, IV bolus injection of 2.5 mg sildenafil. Both subjects had diuretic-refractory ascites with model for end-stage liver disease scores of 25 and 35. Both subjects tolerated IV Sildenafil without side effects. The observed maximum concentrations of plasma sildenafil were 35 and 20.6 ng/ml, with modeled pharmacokinetic estimates for clearance (11.9 and 14.9 L/hr), volumes of distribution (72.8 and 77.3 L) and half-life (4.2 and 3.6 hrs). N-desmethyl sildenafil concentrations ranged from 3 to 40% of the parent concentrations. Our results showed that in CTP class C cirrhosis and renal dysfunction, IV bolus injection of 2.5 mg sildenafil is safe and tolerable.