Citations

BackgroundData on liver transplant (LT) outcomes using deceased donors with heavy drinking (HD) (>2 drinks per day) are scanty.MethodsUsing the United Network for Organ Sharing database (2002-2014), we examined outcomes after LT in adults comparing deceased HD donors with non-HD (ND) donors.ResultsOf 56 182 first LTs performed in the United States for 10 common indications using deceased donors, 47 882 with available information on alcohol use were analyzed. Of these 47 882 LT recipients, 7298 (15%) were from HD donors, with similar proportion over time (2002-2014, Armitage trend testP= 0.75) and for recipient liver disease etiology (χ2P= 0.42). Proportion of liver organ used for LT was lower for HD donors compared with ND donors (63% vs 78%;P< 0.001). Five-year outcomes on first LT comparing 7166 HD donors and 21 498 ND donors matched based on propensity score were similar for liver graft (73.7% vs 73.7%, log rankP= 0.98) and patient survival (77.6% vs 77.0%,P= 0.36). On Cox regression analysis, history of HD in deceased donors did not affect liver graft 1.02 (0.97-1.08) or patient survival 1.03 (0.97-1.09).ConclusionsAmong LT recipients using select liver grafts, history of HD in deceased donors does not impact outcomes after LT.

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.

We examined the Institutional Review Board (IRB) process at 9 academic institutions in the electronic Medical Records and Genomics (eMERGE) Network, for proposed electronic health record-based genomic medicine studies, to identify common questions and concerns. Sequencing of 109 disease related genes and genotyping of 14 actionable variants is being performed in ~28,100 participants from the 9 sites. Pathogenic/likely pathogenic variants in actionable genes are being returned to study participants. We examined each site’s research protocols, informed-consent materials, and interactions with IRB staff. Research staff at each site completed questionnaires regarding their IRB interactions. The time to prepare protocols for IRB submission, number of revisions and time to approval ranged from 10–261 days, 0–11, and 11–90 days, respectively. IRB recommendations related to the readability of informed consent materials, specifying the full range of potential risks, providing options for receiving limited results or withdrawal, sharing of information with family members, and establishing the mechanisms to answer participant questions. IRBs reviewing studies that involve the return of results from genomic sequencing have a diverse array of concerns, and anticipating these concerns can help investigators to more effectively engage IRBs.

Background and Aim: Data are scanty on allocating simultaneous liver kidney (SLK) based on model for end-stage disease (MELD) score. Diabetes mellitus (DM) and hypertension (HTN) are frequent in cirrhosis patients. We analyzed transplant recipients with DM and/or HTN to compare MELD-based outcomes of SLK to liver transplantation alone (LTA). Materials and Methods: Of 13,584 first deceased donor liver transplantation among patients with DM and/or HTN (1530 or 11.2% SLK), MELD score predicted SLK [1.02 (1.01-1.03)]. SLK was beneficial for 5-year patient survival at MELD score ≥43 (78.6% vs. 62.6%, P=0.017), but not at MELD score <29 (74.8% vs. 76.2%, P=0.63). Among 11,405 recipients (976 SLK) at MELD score <29, SLK (n=816) was beneficial compared with 706 LTA [75% vs. 64%, P<0.001; 0.71 (0.55-0.91)] at serum creatinine (SC) ≥2 but not at SC<2 [73% vs. 76%, P=0.32; 0.85 (0.60-1.2)]. Among patients with MELD score 29 to 42, SLK (n=484) and LTA (n=1403) had similar survival [69% vs. 69%, P=0.58; 0.9 (0.7-1.5)]. Among patients with MELD score ≥43, SLK (n=70) was associated with 35% improved patient survival at 5 years compared with 222 LTA [0.65 (0.46-0.93)]. Conclusions: Among patients with DM and/or HTN, SLK is useful at: (a) MELD score <29 and SC≥2 and (b) MELD score ≥43. Prospective studies are needed to confirm these findings as basis to optimize use of SLK.

Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003‐2015). Patient data collected included the type of HE, medications, Model for End‐Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1‐4 months), and longer‐term (6‐12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty‐five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1‐4 and 6‐12 months, respectively. The majority (67%; 8/12) were free from HE‐related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723–731 2016 AASLD.

AbstractBackground & AimsPatients who achieve sustained virological response (SVR) following the treatment of post‐liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known.MethodsWe studied allograft histology in protocol‐based paired liver biopsies in consecutive LT recipients who underwent post‐LT treatment of recurrence of HCV.ResultsA total of 116 patients were treated with interferon‐based therapy for recurrent HCV. Paired pre‐treatment baseline biopsies and post‐treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post‐treatment biopsies vs. 65.5% of patients with non‐response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4–5 year post‐treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage ≥3 on post‐treatment biopsies vs. 37.9% in the non‐response/relapse group (P = 0.001). The 5‐year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2–11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis.ConclusionsIn post‐transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR.