Risk Factors for Hepatitis E Virus Infection and Eating Habits in Kidney Transplant Recipients.

There is a significant risk for ongoing and treatment-resistant courses of hepatitis E virus (HEV) infection in patients after solid organ transplantation. The aim of this study was to identify risk factors for the development of hepatitis E, including the dietary habits of patients. We conducted a retrospective single-center study with 59 adult kidney and combined kidney transplant recipients who were diagnosed with HEV infection between 2013 and 2020. The outcomes of HEV infections were analyzed during a median follow-up of 4.3 years. Patients were compared with a control cohort of 251 transplant patients with elevated liver enzymes but without evidence of an HEV infection. Patients' alimentary exposures during the time before disease onset or diagnosis were assessed. Previous intense immunosuppression, especially treatment with high-dose steroids and rituximab, was a significant risk factor to acquire hepatitis E after solid organ transplantation. Only 11 out of 59 (18.6%) patients reached remission without further ribavirin (RBV) treatment. A total of 48 patients were treated with RBV, of which 19 patients (39.6%) had either viral rebounds after the end of treatment or did not reach viral clearance at all. Higher age (>60 years) and a BMI ≤ 20 kg/m2 were risk factors for RBV treatment failure. Deterioration in kidney function with a drop in eGFR (p = 0.046) and a rise in proteinuria was more common in patients with persistent hepatitis E viremia. HEV infection was associated with the consumption of undercooked pork or pork products prior to infection. Patients also reported processing raw meat with bare hands at home more frequently than the controls. Overall, we showed that the intensity of immunosuppression, higher age, a low BMI and the consumption of undercooked pork meat correlated with the development of hepatitis E.

Daratumumab for the treatment of refractory ANCA-associated vasculitis.

Objective Treatment-refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening condition without evidence-based treatment options. One emerging treatment option for several antibody-mediated autoimmune diseases is the anti-CD38 antibody daratumumab, which depletes autoantibody-secreting plasma cells.Methods We treated two patients with severe life-threatening AAV with renal and pulmonary manifestation despite induction therapy with rituximab and cyclophosphamide with four to eight doses of 1800 mg daratumumab. We followed clinical and immunological responses.Results The first patient with myeloperoxidase-ANCA-positive microscopic polyangiitis had resolution of pneumonitis and pleuritis and stabilisation of kidney function after daratumumab. The second patient with proteinase 3-ANCA-positive granulomatosis with polyangiitis, diffuse alveolar haemorrhage necessitating extracorporeal membrane oxygenation (ECMO) and acute kidney failure, requiring kidney replacement therapy, was weaned off ECMO, mechanical ventilation and dialysis and discharged home after daratumumab. Clinical improvement was paralleled by a strong reduction in serum ANCA levels as well as total IgG, indicating depletion of plasma cells. Apart from the depletion of CD38+ natural killer cells, blood leucocyte levels were not notably influenced by daratumumab. Only mild adverse events, such as hypogammaglobulinaemia and an upper respiratory tract infection occurred.Conclusion Daratumumab was safe and effective in inducing remission in two patients with severe treatment-refractory AAV, warranting prospective clinical trials to establish safety and efficacy.

Impact of first-line use of caplacizumab on treatment outcomes in immune thrombotic thrombocytopenic purpura.

BACKGROUND: The von Willebrand factor-directed nanobody caplacizumab has greatly changed the treatment of immune thrombotic thrombocytopenic purpura (iTTP) in recent years. Data from randomized controlled trials established efficacy and safety. OBJECTIVES: This study aims to address open questions regarding patient selection, tailoring of therapy duration, obstacles in prescribing caplacizumab in iTTP, effect on adjunct treatment, and outcomes in the real-world setting. METHODS: We report retrospective, observational cohorts of 113 iTTP episodes treated with caplacizumab and 119 historical control episodes treated without caplacizumab. We aggregated data from the caplacizumab phase II/III trials and real-world data from France, the United Kingdom, Germany, and Austria (846 episodes, 396 treated with caplacizumab, and 450 historical controls). RESULTS: Caplacizumab was efficacious in iTTP, independent of the timing of therapy initiation, but curtailed the time of active iTTP only when used in the first-line therapy within 72 hours after diagnosis and until at least partial ADAMTS13-activity remission. Aggregated data from multiple study populations showed that caplacizumab use resulted in significant absolute risk reduction of 2.87% for iTTP-related mortality (number needed to treat 35) and a relative risk reduction of 59%. CONCLUSION: Caplacizumab should be used in first line and until ADAMTS13-remission, lowers iTTP-related mortality and refractoriness, and decreases the number of daily plasma exchange and hospital stay. This trial is registered at www. CLINICALTRIALS: gov as #NCT04985318.

Serological Response to Three, Four and Five Doses of SARS-CoV-2 Vaccine in Kidney Transplant Recipients.

Mortality from COVID-19 among kidney transplant recipients (KTR) is high, and their response to three vaccinations against SARS-CoV-2 is strongly impaired. We retrospectively analyzed the serological response of up to five doses of the SARS-CoV-2 vaccine in KTR from 27 December 2020 until 31 December 2021. Particularly, the influence of the different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. In total, 4277 vaccinations against SARS-CoV-2 in 1478 patients were analyzed. Serological response was 19.5% after 1203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% in response to 603 third, 250 fourth, and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7%. In patients with calcineurin inhibitor and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased the serological response rate to 75% in comparison to the no dose adjustment (52%) or dose reduction (46%). Belatacept-treated patients had a response rate of 8.7% (4/46) after three vaccinations and 12.5% (3/25) after four vaccinations. Except for belatacept-treated patients, repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination.

Deep phenotyping: symptom annotation made simple with SAMS.

Precision medicine needs precise phenotypes. The Human Phenotype Ontology (HPO) uses clinical signs instead of diagnoses and has become the standard annotation for patients' phenotypes when describing single gene disorders. Use of the HPO beyond human genetics is however still limited. With SAMS (Symptom Annotation Made Simple), we want to bring sign-based phenotyping to routine clinical care, to hospital patients as well as to outpatients. Our web-based application provides access to three widely used annotation systems: HPO, OMIM, Orphanet. Whilst data can be stored in our database, phenotypes can also be imported and exported as Global Alliance for Genomics and Health (GA4GH) Phenopackets without using the database. The web interface can easily be integrated into local databases, e.g. clinical information systems. SAMS offers users to share their data with others, empowering patients to record their own signs and symptoms (or those of their children) and thus provide their doctors with additional information. We think that our approach will lead to better characterised patients which is not only helpful for finding disease mutations but also to better understand the pathophysiology of diseases and to recruit patients for studies and clinical trials. SAMS is freely available at https://www.genecascade.org/SAMS/.

Predictors of Serological Response to SARS-CoV-2 Vaccination in Kidney Transplant Patients: Baseline Characteristics, Immunosuppression, and the Role of IMPDH Monitoring.

Immunosuppression increases the risk of severe coronavirus disease 2019 (COVID-19). Morbidity and mortality of this disease in kidney transplant patients are higher than in the general population. As the vaccination response of transplant patients is weak, serological monitoring was performed. In this cohort study, we analyzed the determinants of vaccination response. All patients had no history of COVID-19. With anti-spike IgG monitoring, 148 responders and 415 non-responders were identified. We compared both groups using multivariate analyses of the cohort and a sub-cohort of mycophenolic-acid-treated patients. We investigated the influence of patient characteristics, immunosuppression, and erythrocyte inosine monophosphate dehydrogenase (IMPDH) activity. In responders, the time after transplantation was longer (13.5 vs. 8.5 years), the glomerular filtration rate was higher (56.9 vs. 47.8 mL/min/1.73 m2), and responders were younger (53.0 vs. 57.4 years). Heterologous vaccination was more effective than homologous vaccination. Calcineurin inhibitors plus mycophenolate reduced the seroconversion rate. No seroconversion was observed in belatacept patients. In mycophenolate-treated patients, IMPDH activity was a significantly better predictor of response than mycophenolate dose (AUC 0.84 vs. 0.62, p < 0.001). Immunosuppression strongly affects vaccine response. Modifications to immunosuppression should be considered in order to facilitate this response. Erythrocyte IMPDH activity can be used to guide mycophenolate treatment.

First diagnosis of thrombotic thrombocytopenic purpura after SARS-CoV-2 vaccine - case report.

BACKGROUND: We report a case of a 25-year-old male patient, who developed acquired thrombotic thrombocytopenic purpura (aTTP) after receiving a first dose of mRNA-based SARS-CoV-2 vaccine Spikevax (mRNA-1273, Moderna Biotech, USA). While this is the first case in literature describing a case of aTTP after receiving the Spikevax vaccine, there are two other cases after mRNA-based Covid-19 vaccine and two after adenoviral SARS-CoV-2 vaccine. CASE PRESENTATION: The patient presented with persisting malaise, fever, headache, word-finding difficulties, nausea, vomiting, petechial bleeding, and hematuria 13 days after receiving a first dose of vaccination. Laboratory testing showed low platelet count, Coombs-negative hemolytic anemia, and mild acute kidney injury. We excluded vaccine induced immune thrombotic thrombocytopenia (VITT) as another important differential diagnosis and the final diagnosis was established after ADAMTS-13 (A Disintegrin And Metalloproteinase with a ThromboSpondin type 1 motif, member 13) activity was found to be < 1% (reference range > 40%) and ADAMTS-13 antibodies being 72.2 IU/L (reference range < 12 IU/L). We initiated empiric therapy of plasmapheresis and corticosteroids on admission and started caplacizumab the day after. The patient's thrombocyte count normalized 3 days after admission, hemolysis and acute kidney injury resolved after 2 weeks. The patient received 2 doses of rituximab (1 g each) after the diagnosis of immune TTP was established. One month after the initial presentation, the patient is in good overall condition, but still receives daily caplacizumab due to ADAMTS-13 activity of < 1%. CONCLUSIONS: Low platelet count after vaccination against SARS-CoV-2 has gained attraction after vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described as a rare but severe complication of adenoviral-based vaccines. Thrombotic thrombocytopenic purpura (TTP) is an important differential diagnosis, but there are only few reports of TTP following SARS-CoV-2 vaccination. Despite pathophysiological and clinical differences of both entities, diagnostic uncertainty can result in the acute setting, since they share main symptoms such as headache and neurological alterations in addition to thrombocytopenia. In difference to other cases reported, this patient developed first symptoms of TTP as early as 4 days after vaccination, which suggests that vaccination merely acted as trigger for occult TTP, instead of truly inducing an autoimmunological process.

Targeting Cholesterol Metabolism as Efficient Antiviral Strategy Against the Hepatitis E Virus.

BACKGROUND AND AIMS: The Hepatitis E virus hijacks the endosomal system for its release. These structures are highly dependent on cholesterol. Hence, this study investigates the impact of HEV on cholesterol-metabolism, the effect of intracellular cholesterol content on HEV-release and the potential of cholesterol-modulators to serve as antivirals. METHODS: Intracellular cholesterol-content of cells was modulated and impacts on HEV were monitored using qPCR, Western blot, microscopy, virus-titration and density-gradient centrifugation. Blood-lipids and HEV-RNA were routinely quantified in chronically infected patients during follow-up visits. RESULTS: In HEV-infected cells, decreased levels of cholesterol are found. In patients, HEV infection decreases serum-lipid concentrations. Importantly, statin treatment herein increases viral titers. Similarly, reduction of intracellular cholesterol via simvastatin treatment increases viral release in vitro. On the contrary, elevating intracellular cholesterol via LDL or 25-hydroxycholesterol strongly reduces viral release due to enhanced lysosomal degradation of HEV. Drug-induced elevation of intracellular cholesterol via fenofibrate or PSC833 impairs HEV release via the same mechanism. CONCLUSIONS: This study analyses the crosstalk between HEV and intracellular cholesterol. The results highlight the importance of an intact cholesterol homeostasis for HEV-release and thereby identify a potential target for antiviral strategies. Especially fenofibrate is considered a promising novel antiviral against HEV. Beyond this, the study may help clinicians evaluating co-treatments of HEV-infected patients with statins, as this may be counter indicated.

The regulation of interferon type I pathway-related genes RSAD2 and ETV7 specifically indicates antibody-mediated rejection after kidney transplantation.

CONTEXT: Antibody-mediated rejection (ABMR) after kidney transplantation (KTx) remains the crucial obstacle to successful long-term graft function. The identification of gene signatures involved in ABMR could grant the basis for better prevention and treatment strategies. OBJECTIVE: The identification of gene signatures in whole blood cells specific for ABMR after KTx. MATERIALS AND METHODS: Total RNA from blood cells of 16 kidney-transplanted patients with ABMR, stable graft function (SGF), and with T-cell-mediated rejection (TCMR) was isolated. Gene expression was determined by high-throughput sequencing followed by validation and analyses of differentially expressed candidates on mRNA level and on protein level in a large patient cohort (n = 185) in patients with SGF, urinary tract infection (UTI), borderline rejection (BL), TCMR, ABMR, and interstitial fibrosis and tubular atrophy. RESULTS: From the 570 genes detected, 111 discriminated ABMR from SGF and TCMR. A distinct enrichment of interferon (IFN) type I and type II signature gene set was observed. The expression of candidate genes IFIT1, ETV7, and RSAD2 distinguished ABMR patients from patients with SGF and also TCMR, whereas ETV7 and RSAD2 differentiated ABMR also from BL. CONCLUSION: The IFN-inducible genes ETV7 and RSAD2 represent specific biomarkers for ABMR episodes after KTx.

Urinary NGAL-Positive Acute Kidney Injury and Poor Long-term Outcomes in Hospitalized Patients.

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is a widely studied biomarker of renal tubular injury. Urinary NGAL (uNGAL) during acute kidney injury (AKI) predicts short-term adverse outcomes. However, the long-term predictive value is unknown. METHODS: We performed a prospective observational study of 145 patients with hospital-acquired AKI according to Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria and analyzed the long-term predictive value of uNGAL at the time of AKI. We defined a composite outcome of all-cause mortality and the development of end-stage renal disease (ESRD). RESULTS: In all, 61 AKI patients died and 22 developed ESRD within 6 months. The uNGAL levels were significantly higher in patients with poor long-term outcomes. uNGAL levels ≥362 µg/l (highest quartile) and uNGAL levels between 95 and 362 µg/l (third quartile) were associated with hazard ratios of 3.7 (95% confidence interval, 2.1-6.5) and 1.9 (1.1-3.5), respectively, compared with uNGAL levels <95 µg/l (lower quartiles). After 6 months, 67% and 43% of patients within the highest and third uNGAL quartile, respectively, had either progressed to ESRD or died, compared to only 21% of patients with uNGAL in the lower 2 quartiles (P < 0.001). In multivariable Cox regression analyses accounting for conventional predictors, uNGAL was the strongest independent predictor of adverse long-term outcomes. The association of uNGAL levels and poor long-term outcomes remained significant in the subgroup of 107 AKI survivors discharged without requiring dialysis (P = 0.002). DISCUSSION: These data indicate that elevated uNGAL levels at AKI diagnosis predict poor long-term outcomes.

The course of gastric cancer following surgery is associated with genetic variations of the interleukin-1 receptor antagonist and interleukin-1ß.

BACKGROUND: Inflammation, especially the cytokine response of the IL-1 family, has been shown to influence susceptibility to gastric cancer. In addition, several other pro-inflammatory cytokines have been demonstrated to influence metastasis and resistance to chemotherapy. Therefore, genetic variations within these genes may not only affect susceptibility but also influence the outcome of gastric cancer patients. A limited number of studies showed indeed an association of IL-1ß and IL-1RN variations with survival of gastric cancer patients. However, results are inconsistent, possibly because of different patient cohorts and different therapies. METHODS: In this retrospective cohort study we genotyped 154 patients with gastric cancer for IL-1ß and IL-1RN variations. Patients had undergone pathologically proven R0 resection and had received no additional adjuvant treatment. RESULTS: We show here a protective association with disease-free survival for both heterozygous genotypes, IL-1ß SNP C-511T (rs16944) and IL-1RN VNTR. The combination of both heterozygous genotypes is the strongest predictor independent of UICC stage. CONCLUSION: Genetic variations in the IL-1ß and IL-1RN genes influence disease progression in gastric cancer. Screening for these genetic variations might help to stratify therapies for gastric cancer patients in the future.