Study Protocol: A Pilot Study to Determine the Safety and Efficacy of Induction-Therapy, De Novo MPA and Delayed mTOR-Inhibition in Liver Transplant Recipients with Impaired Renal Function. PATRON-Study

<p>Abstract</p> <p>Background</p> <p>Patients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free "bottom-up" regimens in patients with impaired renal function undergoing liver transplantation. This is a single-center study pilot-study (<b>PATRON07</b>) investigating safety and efficacy of CNI-free, "bottom-up" immunosuppressive (IS) strategy in patients undergoing liver transplantation (LT) with renal impairment prior to LT.</p> <p>Methods/Design</p> <p>Patients older than 18 years with renal impairment at the time of liver transplantation eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients in will receive a CNI-free combination therapy (basiliximab, MMF, steroids and delayed Sirolimus). Primary endpoint is the incidence of steroid resistant acute rejection within the first 30 days after LT. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step, 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary endpoint the regimen is regarded to be safe and efficient.</p> <p>Discussion</p> <p>If a CNI-free-"bottom-up" IS strategy is safe and effective, this may be an innovative concept in contrast to classic top-down strategies that could improve the patient short and long-time renal function as well as overall complications and survival after LT. The results of <b>PATRON07 </b>may be the basis for a large multicenter RCT investigating the new "bottom-up" immunosuppressive strategy in patients with poor renal function prior to LT.</p> <p><url>http://www.clinicaltrials.gov</url>-identifier: NCT00604357</p

Potential negative impact of informing patients about medication side effects:a systematic review

Background Pharmacovigilance, as it is carried out primarily by healthcare professionals is more focused on being very objective in nature. Acknowledging the importance of the subjective experience of patients in pharmacovigilance was underpinned by its unique ability to bring about a more holistic understanding through the deep information unraveled by the patients. Medication safety-related information has to be shared with patients to allow them to be actively involved in their therapy and pharmacovigilance. Despite the advantages of sharing information, it stands to reasons whether sharing information related to possible side effects would negatively affect patients and impinge upon their treatment plan and process. Aim of the Review The purpose of this systematic review was to critically assess the potential negative impact of informing patients about medication side effects by written and/or oral information on medication compliance, occurrence/development of suspected side effects and clinical outcomes. Method A comprehensive search was conducted in PubMed, and Cochrane library to identify potential records between the year 1975 and 2017; then titles, abstracts, and full texts were screened using the inclusion criteria to filter out irrelevant studies. The data extraction, and the results were narratively synthesized and presented in tables. Results A total of 2012 articles were screened for inclusion, 32 full-text articles were assessed for eligibility and finally resulting in the inclusion of 17 randomized control studies which met the set criteria. Findings unraveled that the educational intervention did not result in increased occurrence/reporting of side effects in most of the evaluated studies; except 4 studies, and no significant impact on compliance to medications and negative clinical outcome was observed. Apprehension of negative events to medications were observed in two of the four studies which evaluated these parameters. Conclusion The present review did not find enough evidence to support the over concerns on the potential negative impact of sharing of information on the adverse effects to patients, though the influence could manifest as nocebo-effect. The various components and methods employed for this information sharing process can influence the potential impact of this activity. These concerns about the undesirable effects should not deter the active involvement of patients in pharmacovigilance activities. There is a definite need to have more studies in this area, where much of concern still does exist among the various stakeholders of drug safety information. © 2018, Springer Nature Switzerland AG

Interacting signals in the control of hepcidin expression

The amount of iron in the plasma is determined by the regulated release of iron from most body cells, but macrophages, intestinal enterocytes and hepatocytes play a particularly important role in this process. This cellular iron efflux is modulated by the liver-derived peptide hepcidin, and this peptide is now regarded as the central regulator of body iron homeostasis. Hepcidin expression is influenced by systemic stimuli such as iron stores, the rate of erythropoiesis, inflammation, hypoxia and oxidative stress. These stimuli control hepcidin levels by acting through hepatocyte cell surface proteins including HFE, transferrin receptor 2, hemojuvelin, TMPRSS6 and the IL-6R. The surface proteins activate various cell signal transduction pathways, including the BMP-SMAD, JAK-STAT and HIF1 pathways, to alter transcription of HAMP, the gene which encodes hepcidin. It is becoming increasingly apparent that various stimuli can signal through multiple pathways to regulate hepcidin expression, and the interplay between positive and negative stimuli is critical in determining the net hepcidin level. The BMP-SMAD pathway appears to be particularly important and disruption of this pathway will abrogate the response of hepcidin to many stimuli

Immunogenetics of invasive aspergillosis.

Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis