Transplanting Kidney Allografts from Hepatitis C Infected Donors into Hepatitis C Uninfected Recipients: Re-Thinking the Thinker Trial

In the not so distant past, organs from hepatitis C infected donors were either discarded or rarely transplanted into HCV viremic recipients - but never allocated to non-infected patients. However, the simplicity, ease and unprecedented success rates of HCV direct acting antiviral regimens has raised the possibility of utilizing such organs in an attempt to expand the donor pool. The thinker trial reports the first of such attempts. However, caution must be exercised prior to the widespread adoption of such strategy

Granulocyte colony stimulating factor: A potential therapeutic rescue in severe alcoholic hepatitis and decompensated cirrhosis

Liver cirrhosis accounts for over 2 million deaths annually worldwide. A subset of these patients – those with alcoholic hepatitis and decompensated cirrhosis, have abysmal short-term survival. Liver transplant is the only intervention of proven survival benefit; however organ availability is a major limitation. It is thus imperative to assess potential benefit of experimental therapies as a bridge to transplant.Stem cell therapies have shown some promise in patients with end-stage liver disease. Of these, bone-marrow derived hematopoietic stem cells have generated the most interest. Animal as well as human data suggest biological plausibility of stem cell translocation from bone marrow to liver, giving credence to cytokine therapies based on bone marrow stimulation. Granulocyte colony stimulating factor has been the most frequently used cytokine for this purpose. This intervention has shown encouraging results in terms of safety as well as survival benefits in small clinical trials. The evidence, however, is sparse and heterogeneous.In this review we describe the biological plausibility, mechanisms of action, and clinical evidence of the use of cytokine based stem cell therapy in patients with end-stage liver disease

Concordance of sustained virologic response at weeks 4, 12 and 24 post-treatment of hepatitis C in the era of new oral direct-acting antivirals: A concise review

The goal of treatment for chronic hepatitis C viral (HCV) infection is to cure the infection rather than suppress the virus. Historically, a sustained virological response (SVR) defined as undetectable HCV RNA at 24 weeks following the completion of treatment was considered the gold standard to define successful eradication of the virus as a primary endpoint in clinical trials. SVR measured at 12 weeks post-treatment has been shown to be highly concordant with SVR24 in trials of pegylated interferon and ribavirin. The appropriateness and durability of SVR12 as the efficacy endpoint with new oral direct-acting antivirals is less established. A literature search was performed using PubMed, EMBASE and CENTRAL databases to identify any studies that examined the concordance between SVR24 and earlier time points. Two studies and 4 abstracts were found that performed concordance analyses using positive and negative predictive values. Overall, SVR4 and SVR12 were highly concordant with SVR24 with high positive (> 97%) and negative (> 94%) predictive values; however there was a higher risk of HCV relapse occurring after post-treatment week 4. The majority of the data focused on SVR12 and demonstrated that SVR12 reliably predicted SVR24 in several populations infected with HCV (treatment-naïve, prior null responders, different genotypes) using various new oral direct-acting antiviral regimens. In conclusion, the available data suggests that SVR12 is a reliable assessment of HCV eradication and could be used instead of SVR24 for drug development clinical trials assessing efficacy of new direct-acting antivirals. Data on the long-term durability of SVR12 is still needed

Public awareness of acetaminophen and risks of drug induced liver injury: Results of a large outpatient clinic survey.

Acetaminophen is one of the most commonly consumed analgesics world wide. Generally perceived as a safe medication, it is the most common cause of acute liver failure in the United States with inadvertent hepatotoxicity in half of all cases. We therefore conducted a survey on the public perceptions of acetaminophen in patients attending the outpatient clinic in Vancouver, Canada. Among 928 patients who were asked, 765 completed the survey questionnaire. The majority of respondents were female (59%), Caucasian (61%), and educated beyond the secondary school level (81%). 23% reported using acetaminophen at least once a week. A significant minority were unaware of the potential liver toxicity of acetaminophen (24%), and knowledge of hepatotoxicity did not vary with education status. In terms of the medicinal composition of acetaminophen products, over half of the respondents (58%) did not know that extra strength preparations of acetaminophen contained the same drug but in a different dose. This knowledge was more prevalent among those with higher level of education (49% in graduate school educated respondents), but was still low overall. The knowledge that alcohol use with acetaminophen was more harmful was low (43%), but improved with level of education (P for trend 0.03). Among respondents who consumed alcohol regularly, 21% were consuming over 1.5 grams of acetaminophen at a time. These patients had similar harm perception to liver as patients who consumed lower doses of acetaminophen. Overall, in a large, well-educated cohort of patients, knowledge about the adverse effects of acetaminophen, the additional risks with alcohol and composition of various retailed products was suboptimal. We speculate that consumer ignorance is a significant reason why acetaminophen is a leading cause of acute liver failure

Evaluation of a Once-Daily Vancomycin Regimen in an Outpatient Leukemia/Bone Marrow Transplant Clinic (OD-VANCO Study)

ABSTRACTBackground: The Leukemia/Bone Marrow Transplant Program of British Columbia manages patients with high-risk febrile neutropenia and those with non-neutropenic immunocompromised states in an outpatient clinic setting. Because the program treats outpatients only, once-daily administration of IV antibiotics is desirable. A high-dose, once-daily vancomycin nomogram was developed and implemented as part of the antibiotic treatment regimen.Objective: To determine if therapeutic vancomycin trough levels could be achieved with a high-dose, once-daily regimen in this outpatient setting.Methods: A prospective, single-centre, observational cohort study was conducted over a 7-month period. Outpatients in the Leukemia/Bone Marrow Transplant Program were started on IV vancomycin with the high-dose, once-daily vancomycin nomogram, and outcomes were assessed.Results: Of 48 outpatients treated over the 7-month period, 10 (21%) had therapeutic vancomycin trough concentrations (i.e., greater than 10 mg/L). Thirty-five (90%) of the 39 patients with suspected clinical infection experienced clinical cure, and 6 (67%) of the 9 patients with documented microbiological infection experienced microbiological cure. Thirty (62%) of the 48 patients experienced symptoms of “red man syndrome”, and 7 (15%) experienced some degree of nephrotoxicity. Two of 3 patients with laboratory-reported minimum inhibitory concentration (MIC) for identified pathogens had a calculated area under the curve to MIC ratio greater than or equal to 400.Conclusion: The high-dose, once-daily vancomycin nomogram was effective in attaining trough levels greater than 10 mg/L in only 21% of patients in this study. A substantial number of adverse drug reactions were observed. Given these results, high-dose, once-daily vancomycin is no longer recommended for outpatient therapy.RÉSUMÉContexte : Le programme sur la leucémie et la greffe de moelle osseuse de la Colombie-Britannique (Leukemia/Bone Marrow Transplant Program of British Columbia) traite en consultation externe des patients avec une neutropénie fébrile à risque élevé et d’autres en états non neutropéniques d'immunovulnérabilité. Comme le programme s’adresse uniquement à des patients externes, une administration intraveineuse (IV) uniquotidienne d’antibiotiques est souhaitée. Pour cette raison, un nomogramme posologique pour la vancomycine à dose uniquotidienne élevée a été élaboré et mis en place dans le cadre du schéma d’antibiothérapie.Objectif : Déterminer s’il est possible d’atteindre des concentrations minimales thérapeutiques de vancomycine à l’aide d’un schéma thérapeutique à dose uniquotidienne élevée dans ce service de consultation externe.Méthodes : Une étude de cohorte prospective observationnelle a été menée dans un seul centre sur une période de sept mois. Le nomogramme posologique a servi à commencer le traitement IV par la vancomycine à dose uniquotidienne élevée de patients externes participant au programme sur la leucémie et la greffe de moelle osseuse, et les résultats ont été évalués.Résultats : Parmi les quarante-huit patients externes traités pendant une période de sept mois, des concentrations minimales thérapeutiques de vancomycine (c.-à-d. plus de 10 mg/L) ont été atteintes chez dix (21 %) d’entre eux. Trente-cinq (90 %) des trente-neuf patients chez qui l’on soupçonnait une infection clinique ont obtenu une guérison clinique et une éradication microbiologique a été notée chez six (67 %) des neuf patients présentant une infection microbiologique attestée. Trente (62 %) des 48 patients ont présenté un syndrome de l’homme rouge et sept patients (15 %) ont manifesté un certain degré de néphrotoxicité. Deux des trois patients pour qui le laboratoire avait déterminé une concentration minimale inhibitrice (CMI) contre les agents pathogènes en cause avaient un rapport aire sous la courbe sur CMI égal ou supérieur à 400.Conclusion : Le nomogramme posologique pour la vancomycine à dose uniquotidienne élevée a permis d’atteindre des concentrations minimales de plus de 10 mg/L chez seulement 21 % des patients de cette étude. Un nombre considérable d’effets indésirables liés au médicament a été  observé. Compte tenu de ces résultats, il n’est plus recommandé de donner des doses uniquotidiennes élevées de vancomycine à titre de traitement aux patients externes

Posttransplant Lymphoproliferative Disorder in Adults Receiving Kidney Transplantation in British Columbia: A Retrospective Cohort Analysis

Background: Posttransplant lymphoproliferative disorder (PTLD) is a major complication following kidney transplantation. Objective: We undertook this study to characterize PTLD in kidney transplant patients in British Columbia with regard to incidence, patient and graft survival, histological subtypes, treatment modalities, and management of immunosuppression. Design: Retrospective cohort analysis. Setting: British Columbia. Patients: All adult patients who underwent kidney transplantation in British Columbia between January 1, 1996, and December 31, 2012, were included. Patients less than 18 years of age at the time of first transplant and multiple organ transplant recipients were excluded from analysis. Measurements: Patients with lymphoproliferative disorders that occurred subsequent to kidney transplantation were considered to have developed PTLD. Methods: Cases of PTLD were identified by cross-referencing data abstracted from the provincial transplant agency’s clinical database with the provincial cancer agency’s lymphoma registry. Patients were followed up for the development of PTLD until December 31, 2012, and for outcomes of death and graft failure until December 31, 2014. Data collection was completed via an electronic chart review. Results: Of 2217 kidney transplant recipients, 37 (1.7%) developed PTLD. Nine cases were early-onset PTLD, occurring within 1 year of transplant; of these cases, 6 were known/presumed Epstein-Barr virus mismatch, compared with only 2 of 28 late-onset cases. Patient survival for early-onset PTLD was 100% at 2 years post diagnosis. Late-onset PTLD had survival rates of 71.4% and 67.9% at 1 and 2 years, respectively. PTLD was associated with significantly decreased patient survival ( P = .031) and graft survival (uncensored for death, P = .017), with median graft survival of PTLD and non-PTLD patients being 9.5 and 16 years, respectively. Immunosuppressant therapy was reduced in the majority of patients; additional therapies included rituximab monotherapy, CHOP-R, radiation, and surgery. Limitations: Limitations to this study include its retrospective nature and the unknown adherence of patients to prescribed immunosuppressant regimens. In addition, cumulative doses of immunosuppression received and the degree of immunosuppression reduction for PTLD management were not effectively captured. Conclusions: The incidence of PTLD in British Columbia following kidney transplantation was low and consistent with rates reported in the literature. The incidence of late-onset PTLD and its association with reduced patient and graft survival warrant further analysis of patients’ long-term immunosuppression

Interaction of Gender and Hepatitis C in Risk of Chronic Renal Failure After Liver Transplantation

Background. Chronic renal failure (CRF) is a significant cause of morbidity and mortality in post-liver transplantation (LT) recipients. The risk factors associated with the development of renal dysfunction are not clearly elucidated. Objectives. To examine the risk factors in the development of CRF in these patients.Material and methods. Retrospective case-cohort of liver transplant patients without baseline kidney dysfunction who developed chronic renal failure during their follow-up.Results. Of 370 patients, 254 met the inclusion criteria. 30% (76) of these patients had CRF of which 57% (43) were male. Age, estimated glomerular filtration rate (eGFR) at discharge, and HCV infection were found to be risk factors for CRF post-LT. The odds ratio of developing CRF was 1.4 (0.6-3.3) in males with HCV, 1.6 (0.7-3.9) in females without HCV and 4.4 (1.5-13.2) among females with HCV when compared to men without HCV.Conclusions. In this cohort of LT receipients of a major Canadian city, age, eGFR, and HCV infection were risk factors for CRF. Female gender and HCV increased this odds by a factor of more than 4

In-hospital post-transplant acute hepatitis A viral (HAV) infection in a liver transplant recipient who was HAV seropositive pre-transplant

Acute hepatitis A viral (HAV) infection is rare in the liver transplant population due to recommended pre-transplant vaccinations. We report a case of acute hepatitis A infection in a liver transplant recipient. This individual had immunity to hepatitis A with protective IgG antibodies and presented with abnormal liver biochemistry in the post-transplant in-patient setting. Hepatitis A infection was confirmed by positive HAV IgM whereas other etiologies, including acute cellular rejection, were ruled out by laboratory tests and liver biopsies. He was treated conservatively with supportive care and liver enzymes recovered to normal baseline. Despite adequate pre-transplant immunity, in the post-transplant setting there may be loss of protective immunity due to profound immunosuppression and hence hepatitis A should remain an important differential diagnosis in the setting of acute hepatitis

Occult central pontine myelinolysis post liver transplant: A consequence of pre-transplant hyponatremia

Rapid overcorrection of chronic hyponatremia can lead to osmotic demyelination syndrome or central pontine myelinolysis (CPM), a diagnosis often triggered by observing the characteristics of neurological abnormalities developed as a result of CPM. However, anyone with chronic hyponatremia and overcorrection of serum sodium is at risk of physiological CPM despite the lack of clinical symptoms. We report an adult patient who presented as post-op delirium, had incidental finding of CPM by magnetic resonance imaging (MRI) of the head after a liver transplant. Despite his non-typical presentation, the patient had the typical risk factors of CPM such as chronic hyponatremia, rapid overcorrection of serum sodium and cirrhosis undergoing a transplant. As hyponatremia and neurological disorder such encephalopathy simultaneously affect patients with cirrhosis, CPM may be more common than once thought in the chronic liver disease population and inappropriate hyponatremia management has important medical consequences that can go unnoticed

Early Persistent Progressive Acute Kidney Injury and Graft Failure Post Liver Transplantation

Background. Acute kidney injury (AKI) in the setting of liver transplantation is a common and multifaceted complication. Studies in the general population have demonstrated worse prognosis with AKI episodes that persist for a longer duration. Our primary objective was to evaluate the impact of early AKI episodes that are persistent or progressive in nature, on patient outcomes and graft survival. Methods. This was a retrospective cohort study including all patients who received a liver transplant between 2011 and 2015 at our center. Moderate to severe AKI episodes (AKIN II or III) were recorded immediately before transplantation and after surgery until hospital discharge. We evaluated the incidence density rate (IDR) of graft failure and the time to graft failure in patients with persistent or progressive AKI (ppAKI) as compared to controls. Results. Two hundred seventy-nine patients received 301 deceased donor liver allografts. Progressive or persistent AKI was documented in more than half of transplant cases (152/301). The rate of graft loss was 3 times higher in the ppAKI group (25%) versus the controls (8.7%). The IDR of graft failure was 13.79 per 100 case-years in the ppAKI group as compared with 3.79 per 100 case-years in the controls (IDR ratio, 3.64; 95 % confidence interval, 1.88–7.50). After adjusting for hepatic artery thrombosis, ischemic cholangiopathy, infectious complications and Model for End-stage Liver Disease, ppAKI was associated with a decreased graft survival time. Conclusions. Persistent or progressive AKI after liver transplantation is associated with an increased incidence rate of graft failure and is an independent predictor of decreased graft survival time