Jan Beneke

Microparticle generation and leucocyte death in Shiga toxin-mediated HUS

BACKGROUND Shiga toxin-induced haemolytic uraemic syndrome (STEC-HUS) is an acute multisystem disorder characterized by renal failure, neurological dysfunction, haemolysis and intravascular thrombosis. Circulating microparticles originating from a number of cell types including thrombocytes and leucocytes are elevated in paediatric patients. In vitro data also suggest modification of leucocyte death by Shiga toxin. Here, we investigated microparticle generation and leucocyte cell death in vivo in adult STEC-HUS patients during acute disease and recovery. METHODS Multi-colour flow cytometry and immunofluorescence were used to assess microparticle concentration and provenience thrombocyte microparticle seeding to leucocytes and leucocyte cell death in adult STEC-HUS patients treated at a tertiary care centre during the STEC-HUS outbreak in Germany in 2011. RESULTS Plasma microparticle concentrations of both platelet and leucocyte origin were elevated during acute STEC-HUS. Platelet microparticles (MP) were detected on a high proportion of monocytes and granulocytes. Among therapeutic interventions, plasma exchange reduced platelet marker expression on leucocytes, inhibition of complement had only moderate impact on the number of circulating MP and did not alter platelet microparticle binding to leucocytes. Numbers of apoptotic and necrotic monocytes and granulocytes were significantly increased in patients with STEC-HUS compared to healthy controls. Complement inhibition significantly increased the number of circulating apoptotic cells. Monocyte apoptosis on admission was significantly higher in patients subsequently assigned to plasma exchange or admitted to the intensive care unit. CONCLUSIONS In STEC-HUS, elevated numbers of circulating MP and dead leucocytes were detected. Monocyte and granulocyte deaths are novel markers of acute STEC-HUS that may actively contribute to tissue destruction by liberation of pro-inflammatory enzymes and cytokines.

Timing of parathyroidectomy in kidney transplant candidates with secondary hyperparathryroidism: effect of pretransplant versus early or late post-transplant parathyroidectomy

Background The timing of parathyroidectomy in kidney transplant candidates suffering from secondary hyperparathyroidism before versus early or late after transplantation remains controversial. Methods The short‐term follow‐up cohort comprised 66 patients with 1‐year post‐transplant follow‐up, while the long‐term follow‐up cohort contained 123 patients. Risk‐adjusted identification of independent risk factors for compromised renal graft function (KDIGO stage ≥ IV) was performed using multivariable regression analysis adjusted for propensity score logits for parathyroidectomy before versus after renal transplantation. Intra‐individual matched‐pairs analyses were used to identify significant effects of post‐transplant parathyroidectomy on graft function as assessed by estimated glomerular filtration rate (eGFR) and paired t tests. Results Donor kidney function KDIGO stage III (P = .030; OR = 5.191, 95% CI: 1.100–24.508), donor blood group 0 (P = .005; OR = 0.176, 95% CI: 0.048–0.642), and post‐transplant parathyroidectomy (P = .032; OR = 17.849, 95% CI: 1.086–293.268) were revealed as independent significant risk factors for compromised renal graft function in the short‐term follow‐up cohort using propensity score risk adjustment while post‐transplant parathyroidectomy had no independent influence in the long‐term follow‐up cohort (P = .651). Parathyroidectomy after renal transplantation compromised graft function early after parathyroidectomy and at last follow‐up in all post‐transplant parathyroidectomy cases (P ≤ .004). Parathyroidectomy within the first post‐transplant year was associated with compromised renal graft function until last follow‐up (P = .004), while parathyroidectomy late post‐transplant was not. Conclusion Parathyroidectomy should be conducted before transplantation or, if this is not possible, preferably after the first post‐transplant year.

Longterm calcineurin inhibitor therapy and brain function in patients after liver transplantation

Calcineurin inhibitors (CNIs) frequently induce neurological complications early after orthotopic liver transplantation (OLT). We hypothesize that longterm CNI therapy after OLT causes dose‐dependent cognitive dysfunction and alteration of brain structure. In this study, 85 OLT patients (20 with CNI‐free, 35 with CNI low‐dose, and 30 with standard‐dose CNI immunosuppression) underwent psychometric testing and cerebral magnetic resonance imaging approximately 10 years after OLT to assess brain function and structural brain alterations. A total of 33 healthy patients adjusted for age, sex, and education served as controls. Patients receiving CNI showed a significantly worse visuospatial/constructional ability compared with controls (P ≤ 0.04). Furthermore, patients on low‐dose CNI therapy had an overall impaired cognitive function compared with controls (P = 0.01). The tacrolimus total dose and mean trough level were negatively correlated to cognitive function. CNI doses had been adjusted in 91% of the patients in the low‐dose and CNI‐free groups in the past due to CNI‐induced kidney damage. Patients treated with CNI showed significantly more white matter hyperintensities (WMH) than patients on CNI‐free immunosuppression and controls (P < 0.05). Both the mean cyclosporine A and tacrolimus trough levels correlated significantly with WMH. In conclusion, longterm CNI therapy carries a risk of cognitive dysfunction especially in patients who already showed nephrotoxic side effects indicating an increased susceptibility of these patients against toxic CNI effects. This subgroup of patients might benefit from a change to CNI‐free immunosuppression. Liver Transplantation 24 56–66 2018 AASLD.

Hangzhou criteria are more accurate than Milan criteria in predicting long-term survival after liver transplantation for HCC in Germany

BackgroundMilan criteria are used for patient selection in liver transplantation for hepatocellular carcinoma (HCC). Hangzhou criteria have been shown in China to enable access to liver transplantation for more patients when compared to Milan criteria without negative effects on long-term survival. The purpose of this study was to evaluate the Hangzhou criteria in a German cohort.MethodsOne hundred fifty-nine patients transplanted for HCC between 1975 and 2010 were investigated. Patients were categorized into four groups depending on the fulfillment of Milan and Hangzhou criteria. General and tumor baseline characteristics were compared. Overall and tumor-free survival rates were investigated with the Kaplan-Meier analysis.ResultsOne-, 3-, 5-, and 10-year survival rates for patients fulfilling Milan criteria (n = 68) were 89.7, 83.7, 75.8, and 62.1%, respectively, versus 89.8, 82.2, 75.2, and 62.6% for patients fulfilling Hangzhou criteria (n = 109) (p = 0.833). When comparing patients exceeding Milan or Hangzhou criteria, survival rates were 75.3, 53.2, 48.1, and 41.1% versus 63.3, 31.4, 26.9, and 22.1%, respectively (p = 0.019). The comparison of tumor-free survival rates in patients fulfilling Milan or Hangzhou criteria was statistically not significant (p = 0.785), whereas the comparison of the groups exceeding the criteria showed significantly worse survival for patients outside Hangzhou criteria (p = 0.007). The proportion of patients fulfilling Hangzhou criteria (68.6%) was significantly larger as compared to the proportion fulfilling Milan criteria (42.8%) (p < 0.001).ConclusionHangzhou criteria are more accurate in predicting long-term survival after liver transplantation for HCC in Germany. Deployment of the Hangzhou criteria for patient selection could enlarge the pool of transplantable patients.

Evaluation of published assessment tools for comorbidity in liver transplantation: a systematic review protocol

Introduction Liver transplantation is considered the best therapy option for end-stage liver disease. Different factors including recipient comorbidity at time of transplantation are supposed to have substantial impact on outcomes. Although several studies have focused on comorbidity assessment indices for liver transplant recipients, there is no systematic review available on the methodological details and prognostic accuracy of these instruments. The aim of this study is to systematically review recipient comorbidity assessment indices in the context of liver transplantation. Methods and analysis PubMed, Embase, Web of Science and PsyINFO databases will be searched. Studies describing, using or evaluating specific assessment tools to predict the effect of comorbidity on clinical outcomes after liver transplantation will be included. The selection will be conducted independently by two reviewers. The study characteristics and methodological information on published comorbidity assessment tools will be extracted into a predefined structural table. This approach will be deployed to systematically extract information on the validity, reliability and practical feasibility of investigated comorbidity assessment tools for comparative evaluation. Narrative information synthesis will be conducted, and additional meta-analytical comparison will be performed, if appropriate. Ethics and dissemination All data are collected from published literature. Thus, formal ethics review for the research is not required. The findings of this systematic review will be published in a peer-reviewed journal and presented at relevant conferences. The results of this systematic review will be highly relevant for further research on prognostic models, clinical decision making and optimisation of donor organ allocation. PROSPERO registration number CRD42017074609.

Clinical and Laboratory Consequences of Platelet Transfusion in Shiga Toxin-Mediated Hemolytic Uremic Syndrome.

Recent studies suggest that platelet transfusions are harmful in patients with thrombotic thrombocytopenic purpura, an entity of thrombotic microangiopathies. As the typical or Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome (STEC-HUS) is also classified as thrombotic microangiopathy, we complement these data with an analysis of 250 patients from the German O104:H4 STEC-HUS outbreak. The effect of platelet transfusion in 44 patients who received platelet transfusions vs 206 control patients was investigated. Criteria for both groups were severe thrombocytopenia less than 50/nL, severe hemolysis with administration of packed red blood cells, and a complicated clinical course with admission to intensive care units. Readouts were clinical complications and changes in routine clinical chemistry and whole blood count. Chemistry values at admission and demographic parameters were comparable. Platelet transfusions were administered in 44 cases a median of 7 (interquartile range, 6-9) days after diarrhea onset. After platelet transfusion, we observed a transient and slight increase in inflammation parameters. No significant difference in major complications such as seizures, or requirement for ventilation or renal replacement therapy could be observed. Thrombotic events such as thrombosis or embolism were comparably rare in both groups (2.3% in platelet transfused vs 4.4% in controls, P=not significant). The mortality was not significantly different (0% vs 2.6%, P=not significant) in our study cohort, but overall in the outbreak, 6 of 711 STEC-HUS patients in Germany died of a procedural-related bleeding complications. In conclusion, platelet transfusions seem comparably safe in adult STEC-HUS patients, considering both the possible necessity for invasive procedures and potential risk for severe bleeding.

Risk-factors for nodular hyperplasia of parathyroid glands in sHPT patients

Introduction Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG. Material and methods One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG. Results Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773–0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG. Conclusions The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.