Improving adherence to immunosuppression after liver or kidney transplantation in individuals with impairments in personality functioning - A randomized controlled single center feasibility study.

Introduction: Although adherence to immunosuppressive medication is the key factor for long-term graft survival today, 20-70% of transplant recipients are non-adherent to their immunosuppressive medication. Objective: A prospective, randomized, controlled single-center feasibility study was designed to evaluate the impact of a step guided multicomponent interprofessional intervention program for patients after kidney or liver transplantation on adherence to their immunosuppressive medication in daily clinical practice. Materials and methods: The intervention consisted of group therapy and daily training as well as individual sessions in a step guided approach. The primary endpoint of the study was adherence to immunosuppression as assessed with the "Basel Assessment of Adherence to Immunosuppressive Medications Scale" (BAASIS). The coefficient of variation (CV%) of Tacrolimus (TAC) through levels and the level of personality functioning was a secondary endpoint. We conducted six monthly follow-up visits. Results: Forty-one age- and sex-matched patients [19 females, 58.5 (SD = 10.56) years old, 22 kidney- and 19 liver transplantation] were randomized to the intervention- (N = 21) or control-group (N = 20). No differences between intervention- and control groups were found in the primary endpoint adherence and CV% of TAC. However, in further exploratory analyses, we observed that individuals with higher impairments in personality functioning showed higher CV% of TAC in the controls. The intervention might compensate personality-related susceptibility to poor adherence as evident in CV% of TAC. Discussion: The results of the feasibility study showed that this intervention program was highly accepted in the clinical setting. The Intervention group could compensate higher CV% of TAC after liver or kidney transplantation in individuals with lower levels of personality functioning and non-adherence. Clinical trial registration: ClinicalTrials.gov, identifier NCT04207125.

COVID-19 Pandemic Stress-Induced Somatization in Transplant Waiting List Patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in widespread socioeconomic restrictions including quarantine, social distancing and self-isolation. This is the first study investigating the psychological impact of the pandemic on patients waiting for liver or kidney transplantation, a particularly vulnerable group. Methods: Twenty-seven patients on the transplantation waiting list and 43 healthy controls took part in an online survey including the Beck Depression Inventory (BDI-2), the Brief Symptom Inventory-18 (BSI-18), the Pittsburgh Sleep Quality Index (PSQI), the Alcohol Use Identification Test (AUDIT-C), the 12-item Operationalized Psychodynamic Diagnosis Structure Questionnaire (OPD-SQS) and a questionnaire to determine cognitions and beliefs, attitude and fear related to COVID-19. Results: BSI-18 Somatization was increased in waiting list patients compared to controls. Correlation analyses indicated a relationship between Somatization and the fear of contracting the coronavirus in the patient group; however this association was weak. In patients and controls, other psychologicial symptoms (depression, anxiety) correlated highly with emotional distress due to social distancing. There were no differences between patients and controls in depression scores and sleep disturbances. Alcohol consumption and personality structure were not related to COVID-19 fears. Conclusion: In times of the first lockdown during the COVID-19 pandemic, patients on the transplantation waiting list have high somatization symptoms associated with COVID-19 fears. As vulnerable group, they need psychological counseling to improve mental well-being during times of crisis.

Effects of both Pro- and Synbiotics in Liver Surgery and Transplantation with Special Focus on the Gut-Liver Axis-A Systematic Review and Meta-Analysis.

The gut-liver axis is of upmost importance for the development of infections after surgery. Further bacterial translocation due to surgery-related dysbiosis is associated with limited detoxification function of the liver compromising outcome of surgical therapy. After liver surgery, about 30% of patients develop a bacterial infection, with the risk of bacteremia or even sepsis-associated liver failure and mortality in >40%. The potential benefit of pro-/synbiotics given before surgery is still under debate. Thus, a systematic literature search on trials comparing patients with or without supplementation and outcome after liver resection or transplantation was performed. Our search strategy revealed 12 relevant studies on perioperative administration of pro-/synbiotics in liver surgery. The pro-/synbiotic combinations and concentrations as well as administration timeframes differed between studies. Five studies were performed in liver transplantation and 7 in liver resection. All studies but one reported lower infection rates (pooled RR: 0.46, 95% CI: 0.31-0.67) with pro-/synbiotics. Liver function was assessed after LT/LR in 3 and 5 studies, respectively. Pro-/synbiotics improved function in 1/3 and 2/5 studies, respectively. Concluding, perioperative pro-/synbiotics clearly reduce infection after liver surgery. However, standard protocols with both well-defined probiotic strain preparations and administration timeframes are pending.

The Graz Liver Allocation Strategy-Impact of Extended Criteria Grafts on Outcome Considering Immunological Aspects.

Background: Transplant centers are forced to use livers of extended criteria donors for transplantation due to a dramatic organ shortage. The outcome effect of extended donor criteria (EDCs) remains unclear. Thus, this study was designed to assess the impact of EDCs on outcome including immunological aspects after liver transplantation (LT). Patients and Methods: Between November 2016 and March 2018, 49 patients (85.7% male) with a mean age of 57 ± 11 years underwent LT. The impact of EDCs on outcome after LT was assessed retrospectively using both MedOcs and ENIS (Eurotransplant Network Information System). Results: About 80% of grafts derived from extended criteria donors. Alanine aminotransferase/aspartate aminotransferase (AST/ALT) levels elevated more than three times above normal values in organ donors was the only significant risk factor for primary dysfunction (PDF) and primary non-function (PNF)/Re-LT and early non-anastomotic biliary strictures (NAS). Balance of risk (BAR) score did not differ between EDC and non-EDC recipients. PDF (14.3% of all patients) and PNF (6.1% of all patients) occurred in 23.1% of EDC-graft recipients and in 10.0% of non-EDC-graft recipients (RR 2.31, p = 0.663). The 90-day mortality was 3.6%. There was no difference of early non-anastomotic biliary tract complications and biopsy proven rejections (BPR). There was no correlation of PDF/PNF with BPR and NAS, respectively; however, 66.7% of the patients with BPR also developed early NAS (p < 0.001). Conclusion: With the Graz liver allocation strategy, excellent survival can be achieved selecting livers with no more than 2 not outcome-relevant EDCs for patients with MELD >20. Further, BPR is associated with biliary complications.

Immunosuppression with generic tacrolimus in liver and kidney transplantation-systematic review and meta-analysis on biopsy-proven acute rejection and bioequivalence.

While rejection prevention with innovator tacrolimus (Tac) is one of the key factors for long-lasting graft function, the use of generic Tac is still under debate. Thus, we performed a systematic review and meta-analysis to provide an overview on the current body of evidence for the effect of generic Tac in adult liver (LT) and kidney transplantation (KT) with focus on both biopsy-proven acute rejection (BPAR) and bioequivalence. A systematic literature search for trials comparing generic versus innovator Tac was conducted accordingly. Seventeen studies (5 LT, 11 KT, 1 LT/KT) including 1412 patients were identified. About 92.9% (13/14; 5/5 LT, 8/9 KT) of studies reported the same or lower BPAR with generics (pooled RR: 0.84, 95% CI: 0.65-1.09); however, de novo studies showed a significantly lower risk with generic Tac (RR: 0.75, 95% CI: 0.63-0.90), whereas conversion studies showed increased risk (RR: 1.93, 95% CI: 1.00-3.70). Bioequivalence was demonstrated primarily in studies on conversion. The current evidence is mostly based on observational data and studies showing some risk of bias. In conclusion, whereas overall there was no significant difference in terms of BPAR, there is some evidence suggesting lower BPAR risk with generic Tac for de novo use.

A prospective, randomized, single-blind, multicentre, phase III study on organ preservation with Custodiol-N solution compared with Custodiol® solution in organ transplantation (kidney, liver and pancreas).

BACKGROUND: Organ preservation before transplantation is still a challenge. Both the University of Wisconsin and Bretschneider's histidine-tryptophan-ketoglutarate (HTK; Custodiol®) solution are standard for liver, kidney and pancreas preservation. Organ preservation with both solutions is comparable; recently, however, Custodiol® solution has been modified to Custodiol-N according to the needs of today. Thus, our study was defined to study its effect in clinical transplantation. METHODS: Patients undergoing kidney transplantation (n = 412) (including approximately 30 combined kidney-pancreas) or liver transplantation (n = 202) receive grafts that have been cold stored in either Custodiol® or Custodiol-N to demonstrate noninferiority of Custodiol-N regarding both graft function and graft injury after transplantation. DISCUSSION: Preclinical data have clearly shown that Custodiol-N is superior to Custodiol® in cold static organ preservation via mechanisms including inhibition of hypoxic cell injury, cold-induced cell injury and avoidance of adverse effects during warm exposure to the solution. Further clinical safety data on Custodiol-N for cardioplegia are available. Thus, this study was designed to compare Custodiol® with Custodiol-N for the first time in a prospective, randomized, single-blinded, multicentre, phase III clinical transplantation trial. TRIAL REGISTRATION: Eudra-CT, 2017-002198-20. Registered on 28 November 2018.

Both sarcopenia and frailty determine suitability of patients for liver transplantation-A systematic review and meta-analysis of the literature.

Liver grafts are allocated based on both urgency and utility. Due to a tremendous shortage of suitable organs for liver transplantation (LT), a careful selection of suitable recipients is of utmost importance. While the sickest first principle for organ allocation based on MELD score goes along with poor utility, other parameters reflecting the general health condition like frailty and sarcopenia might be essential to detect suitable patients for the waiting list. Thus, this study was designed to evaluate both frailty and sarcopenia in LT. A systematic review of the literature on sarcopenia and frailty measurements in liver transplant recipients was performed. Thirteen of 238 studies were selected for full paper review. Six of the studies investigating the impact of frailty on waitlist mortality were subjected to a meta-analysis. Despite the different methodologies to assess sarcopenia, reports showed that sarcopenia was highly related to waitlist mortality with a sum of all that highly favored negative outcome in case of sarcopenia. The existing literature clearly underlines that frailty and sarcopenia are important to determine in LT candidates. One unique index for transplant candidates reflecting frailty should be developed and be used as a standard in all transplant centers to facilitate comparability.

Control of Ischemia-Reperfusion Injury in Liver Transplantation: Potentials for Increasing the Donor Pool.

BACKGROUND: Organ shortage is a growing problem, with a rising number of organs being harvested from extended criteria donors, and this trend will further continue to increase as organ donors are getting older and have more comorbidities. Since this fact is immutable, efforts have been made to reduce the extent of ischemia-reperfusion injury (IRI) as well as of direct and indirect harvest-related graft injury which affects all organs in a more or less distinct way. METHODS: In liver transplantation (LT), the activation of Kupffer cells during organ reperfusion, thus provoking microcirculatory disturbances, hypoxia, and endothelial cell injury, is one of the key mechanisms causing graft dysfunction. Multiple approaches have been taken in order to find efficient preconditioning methods by pharmacological pretreatment, controlled induction of ischemia, controlled denervation of donor organs, and reconditioning with machine perfusion to prevent IRI, whereas marginal organs (i.e. steatotic grafts) are especially vulnerable. RESULTS: The above-mentioned approaches have been pursued in experimental and clinical settings. At this time point, however, there is not yet enough clinical evidence available to recommend any particular drug pretreatment or any other intervention for organ preconditioning prior to transplantation. CONCLUSION: The multifactorial pathophysiology in the setting of IRI in LT requires a multimodal therapeutic approach with the integration of pharmacological and technical means being applied to the donor, the organ per se, and the recipient. Currently, there is no consensus on standardized pretreatment of donor organs in order to improve the transplant outcome.

Using Multiple Outcomes of Sexual Behavior to Provide Insights Into Chlamydia Transmission and the Effectiveness of Prevention Interventions in Adolescents.

BACKGROUND: Mathematical models are important tools for assessing prevention and management strategies for sexually transmitted infections. These models are usually developed for a single infection and require calibration to observed epidemiological trends in the infection of interest. Incorporating other outcomes of sexual behavior into the model, such as pregnancy, may better inform the calibration process. METHODS: We developed a mathematical model of chlamydia transmission and pregnancy in Minnesota adolescents aged 15 to 19 years. We calibrated the model to statewide rates of reported chlamydia cases alone (chlamydia calibration) and in combination with pregnancy rates (dual calibration). We evaluated the impact of calibrating to different outcomes of sexual behavior on estimated input parameter values, predicted epidemiological outcomes, and predicted impact of chlamydia prevention interventions. RESULTS: The two calibration scenarios produced different estimates of the probability of condom use, the probability of chlamydia transmission per sex act, the proportion of asymptomatic infections, and the screening rate among men. These differences resulted in the dual calibration scenario predicting lower prevalence and incidence of chlamydia compared with calibrating to chlamydia cases alone. When evaluating the impact of a 10% increase in condom use, the dual calibration scenario predicted fewer infections averted over 5 years compared with chlamydia calibration alone [111 (6.8%) vs 158 (8.5%)]. CONCLUSIONS: While pregnancy and chlamydia in adolescents are often considered separately, both are outcomes of unprotected sexual activity. Incorporating both as calibration targets in a model of chlamydia transmission resulted in different parameter estimates, potentially impacting the intervention effectiveness predicted by the model.

Calcification score evaluation in patients listed for renal transplantation.

Based on native CT scans of the pelvic region using a standardized calcification score, evaluation of iliac vascular calcification was performed between 2008 and 2012 prior to listing for renal transplantation in 205 patients with chronic kidney disease. Vascular calcification showed a decrease from proximal to distal. The difference between the degree of calcification in the common iliac artery and in the external iliac artery was significant (P<.001). Risk factors for total iliac vascular calcification were age, smoking, sex, underlying renal disease, and diabetes. Multivariate analysis revealed age to be the most relevant risk factor (P<.001). The duration of hemodialysis correlated significantly with total iliac vascular calcification. As the introduction of the standardized surgical evaluation protocol, no transplantation has had to be broken off and no early graft loss due to calcification has occurred. Thus, careful scoring of vascular calcification prior to transplantation may be a valuable tool to support surgical decisions and to improve patient safety and outcome in increasingly older transplant recipients.

Comprehensive Review on Custodiol-N (HTK-N) and its Molecular Side of Action for Organ Preservation.

BACKGROUND: The later fate of a graft is highly dependent on its initial quality. Aside from that the three predominant phases during transplantation (Tx) organ retrieval, cold static preservation and reperfusion cause in a direct and indirect manner graft injury. There is complex ischemia reperfusion injury (IRI) triggered during the whole process of Tx which contributes to further damage of the graft. METHODS: The today's organ preservation with commercially available solutions that all have toxic potential per se is still imperfect. Thus, improved preservation solutions are desperately needed to be able to even safely preserve grafts from extended criteria donors which are more susceptible to especially IRI. Most recently, a modified less toxic histidine-tryptophan-ketoglutarate (HTK; Custodiol®) the so called histidine-tryptophan-ketoglutarate-N (HTK-N) for both better cardioplegia and organ preservation for Tx has been developed. It is characterized as an electrolyte balanced, iron chelatorsupplemented, and amino acid-fortified organ preservation solution with replaced buffer ameliorating resistance to injury during the cold static preservation with subsequent IRI. Numerous in vitro and in vivo experiments have shown the superiority of the HTK-N solution in ROS generation, microcirculation, and subsequent inflammatory response compared with HTK. RESULTS: According to data available to date, HTK-N has both lower cytotoxicity and higher protective potential than HTK. First clinical studies on both HTK-N for cardioplegia in cardiac surgery and for organ preservation for transplantation have been performed or are ongoing. CONCLUSION: In this review, the novelty and composition of HTK-N and studies investigating the potential of this new solution are focussed, after summarizing the most relevant molecular mechanisms of IRI.

Behavioral and community correlates of adolescent pregnancy and Chlamydia rates in rural counties in Minnesota.

Identifying co-occurring community risk factors, specific to rural communities, may suggest new strategies and partnerships for addressing sexual health issues among rural youth. We conducted an ecological analysis to identify the county-level correlates of pregnancy and chlamydia rates among adolescents in rural (nonmetropolitan) counties in Minnesota. Pregnancy and chlamydia infection rates among 15-19 year-old females were compared across Minnesota's 87 counties, stratified by rural/urban designations. Regression models for rural counties (n = 66) in Minnesota were developed based on publicly available, county-level information on behaviors and risk exposures to identify associations with teen pregnancy and chlamydia rates in rural settings. Adolescent pregnancy rates were higher in rural counties than in urban counties. Among rural counties, factors independently associated with elevated county-level rates of teen pregnancy included inconsistent contraceptive use by 12th-grade males, fewer 12th graders reporting feeling safe in their neighborhoods, more 9th graders reporting feeling overweight, fewer 12th graders reporting 30 min of physical activity daily, high county rates of single parenthood, and higher age-adjusted mortality (P < .05 for all associations). Factors associated with higher county level rates of chlamydia among rural counties were inconsistent condom use reported by 12th-grade males, more 12th graders reporting feeling overweight, and more 12th graders skipping school in the past month because they felt unsafe. This ecologic analysis suggests that programmatic approaches focusing on behavior change among male adolescents, self-esteem, and community health and safety may be complementary to interventions addressing teen sexual health in rural areas; such approaches warrant further study.

Social isolation and depression predict 12-month outcomes in the "waiting for a new heart study".

BACKGROUND: Identification of modifiable psychosocial characteristics related to survival of heart transplant (HTx) candidates is needed to prevent clinical deterioration and improve prognosis. METHODS: A multi-site, prospective study was conducted with 318 HTx candidates (18% female, 82% male; 53 +/- 11 years of age) newly listed at 17 hospitals in Germany and Austria. Baseline demographic and psychosocial characteristics were assessed by questionnaires. Indicators of disease severity (Heart Failure Survival Score, creatinine, cardiac index) and 12-month outcomes (death, high-urgency HTx, elective HTx, de-listing due to deterioration or improvement) were provided by Eurotransplant. RESULTS: By 12 months, 33 patients died, 83 received an urgent HTx, 30 underwent an elective HTx, and 9 were de-listed due to clinical deterioration and 17 due to improvement. All measures of disease severity predicted outcomes. Controlling for disease severity, the number of social contacts contributed significantly to outcomes, favoring those who improved. Comparing socially isolated patients (<4 social contacts/month) who also had depression scores in the clinical range (high psychosocial risk group; n = 37) to those with >10 social contacts/month without depression (low psychosocial risk group; n = 47) revealed significant differences in the distribution of outcome frequencies (chi-square = 11.2, df = 4, p < 0.04). The high psychosocial risk group was more likely to have died/deteriorated and less likely to have improved than the low psychosocial risk group. CONCLUSIONS: Regardless of disease severity, socially isolated HTx candidates who are also depressed may be at increased risk for clinical deterioration and mortality, indicating a need for psychosocial intervention.

Retroperitoneal pancreas transplantation with systemic-enteric drainage--case report.

Enteric drainage and intraperitoneal graft position is the preferred technique for pancreas transplantation at most transplant centers. The technique of retroperitoneal pancreas transplantation was first described by Boggi et al. [Transplantation,79 (2005), 1137]. In this case report, a modified model of retroperitoneal pancreas transplantation with systemic-enteric drainage is presented. A 48-yr-old patient underwent combined retroperitoneal pancreas and kidney transplantation because of type-I-diabetes, and diabetic nephropathy. At the time of transplantation, the patient had a body mass index of 31 and severe atherosclerosis of the iliac vessels. After mobilization of the colon and mesocolon ascendens, the vessels of the pancreas graft were anastomosed end-to-side to the aorta and to the inferior caval vein of the recipient. For exocrinous drainage, a side-to-side duodenojejunostomy was performed after bringing a jejunal loop through a window in the right colon mesentery. The graft was in a retroperitoneal position. The patient was insulin-independent after 48 h, the lipase and amylase levels were within the normal range. The first experience with retroperitoneal pancreas transplantation with systemic-enteric drainage showed that the technique was safe and had technical advantages when compared with the classic method.

Establishing extracorporeal membrane oxygenation in a university clinic: case series.

OBJECTIVES: Although extracorporeal membrane oxygenation (ECMO) is well established for respiratory failure in neonates, application in adults is still considered controversial. The survival of patients with acute respiratory distress syndrome and ECMO therapy is 50% to 70%. DESIGN: A retrospective analysis of 10 patients, who were placed on ECMO from September 2004 to December 2005, was performed. SETTING: University clinic. INTERVENTIONS: Venoarterial ECMO was established in 7 patients, venovenous ECMO in 2 patients, and combined venoarterial and venovenous ECMO in 1 patient. MEASUREMENTS AND MAIN RESULTS: Indications were pneumonia, acute respiratory distress syndrome, near drowning, pericardial tamponade with shock lung, right-heart failure after heart transplantation, shock lung after cardiopulmonary resuscitation, and right-heart failure in chronic thromboembolic pulmonary hypertension. Median maintenance of ECMO therapy was 56.5 hours (range, 36-240). The median Murray score was 3.3 for survivors and 4 for nonsurvivors. Overall mortality was 30%; 70% were weaned from ECMO and survived until discharge. Median pre-ECMO risk for fatal outcome according to Hemmila was 0.43 for survivors and 0.92 for nonsurvivors (p < 0.02). In 2 cases, surgical reintervention was necessary because of bleeding in one, and a side switch of the cannulae had to be performed because of femoral venous thrombosis in the other. CONCLUSIONS: ECMO has been shown to be a successful therapy for acute respiratory distress syndrome when conventional strategies have failed. Pre-ECMO risk assessment may be useful in the evaluation of patients.

Incisional hernia following liver transplantation: incidence and predisposing factors.

BACKGROUND: Patients after orthotopic liver transplantation (OLT) have a high risk of developing incisional hernia (IH). In the literature incidences between 5% and 17% are reported. PATIENTS AND METHODS: In 90 patients, who underwent OLT between October 1998 and December 2005, a retrospective analysis on the occurrence of IH was performed. Surgical access for OLT was a transversal upper laparotomy. Age, gender, primary disease, ICU stay, immunosuppressive regimen and two different closure techniques (running suture or single sutures in layers) were evaluated. RESULTS: In 73 patients (76.7%, group 2) healing of the incision was without problems, in 17 patients (23.3%, group 1), IH occurred. Total survival was similar between the groups (86.3% vs. 94.1%, n.s.). No significant differences between the groups concerning age, gender, body mass index, platelet count and duration of ICU stay were found. Also, the technique of abdominal closure had no impact on the development of IH. No IH was found in patients with hepatocellular carcinoma (n = 15), whereas end-stage liver cirrhosis (n = 75) was associated with development of IH (p = 0.064). Multivariate analysis revealed end-stage liver cirrhosis, Sirolimus, and MMF to be independent significant risk factors for IH after OLT. CONCLUSION: IH following OLT has to be regarded a frequent complication. While technique of abdominal closure seems to have no impact, primary diagnosis and kind of immunosuppressive regimen exerted a significant influence on the formation of IH.