Evaluation of discriminative capacity of two formulas of CKD-EPI to predict complications after the first episode of heart failure with preserved ejection fraction.

Background: Determining the prognosis of heart failure with preserved ejection fraction (HFpEF) is problematic, as the ejection fraction cannot be used. Formulae that estimate glomerular filtration rate (eGFR) may be potential prognosticators for this condition, since renal dysfunction is a well-known predictor of poor outcomes of all forms of heart failure. Methods: A prospective observational study of 117 HFpEF patients (average age 71.6±9.1 years; 65.8% women) who had eGFR determined after their first episode of cardiac decompensation by two different chronic kidney disease epidemiology collaboration (CKD-EPI) equations. The ability to predict hospitalizations and mortality over 24 months by the two equations were compared. Results: The CKD-EPI formula based on serum creatinine only performed poorly. However, the CKD-EPI equation that used both serum creatinine and serum cystatin C was associated with unfavorable outcome: eGFR <45 mL/min/1.73 m2 predicted 24-month mortality (HR=4.21 [1.32;13.43], p=0.02) and the combined endpoint of mortality and hospitalization (HR 2.45 [1.42;4.22], p=0.001). . Conclusions: eGFR by the CKD-EPI equation based on serum creatinine and cystatin C levels, but not by the CKD-EPI creatinine only equation, predicts the outcome of HFpEF patients.

Adverse outcomes in obstetric-atypical haemolytic uraemic syndrome: a case series analysis.

Objective: The aim of this case series is to raise awareness of obstetric-related atypical haemolytic uraemic syndrome (aHUS) amongst obstetricians and gynaecologists. Study design: Data from 20 consecutive patients, aged 19-38, with obstetric-aHUS manifestation during or immediately after pregnancy are reported. Patients were diagnosed and treatment was initiated between 2012 and 2016. Results: Presentation of aHUS was mainly preceded by preeclampsia and/or haemolysis, elevated liver enzymes and low platelet count syndrome, other obstetric complications, or by diarrhoea. Thrombotic microangiopathy (TMA) was evident in all patients with signs of microangiopathic haemolysis (sharp decline in haemoglobin; mean 67 g/L), elevated lactate dehydrogenase (LDH; mean 2953.1 U/L), schistocytosis, thrombocytopenia (mean platelet count 52.5 × 109/µL), and acute kidney injury (AKI) (hypercreatininaemia, mean 456.4 µmol/L; oliguria or anuria). The majority of patients (80%) initially presented with arterial hypertension. Diagnosis of obstetric-aHUS was complicated, as multiple organs were affected. Time taken to make the diagnosis of aHUS delayed the initiation of fresh-frozen plasma infusions and plasma exchange (80% of patients) and subsequent eculizumab treatment (40% of patients). Maternal mortality was high (35%) as was foetal mortality (25%). Conclusions: Obstetric-aHUS is a serious condition characterized by multiple organ failure (MOF) and a high mortality rate. Presentation of obstetric-aHUS is preceded by various precipitating factors, suggesting pregnancy complications, and not the pregnancy per se, often induce aHUS in women with a genetic predisposition to its development. A delay in the correct diagnosis and initiation of the most effective treatment can have serious consequences, reinforcing the need to raise awareness of obstetric-aHUS.

Therapeutic Complement Targeting in ANCA-Associated Vasculitides and Thrombotic Microangiopathy.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of systemic autoimmune disorders characterized by necrotizing inflammation of medium-to-small vessels, a relative paucity of immune deposits, and an association with detectable circulating ANCAs. AAVs include granulomatosis with polyangiitis (renamed from Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Until recently, AAVs have not been viewed as complement-mediated disorders. However, recent findings predominantly from animal studies demonstrated a crucial role of the complement system in the pathogenesis of AAVs. Complement activation or defects in its regulation have been described in an increasing number of acquired or genetically driven forms of thrombotic microangiopathy. Coinciding with this expanding spectrum of complement-mediated diseases, the question arises as to which AAV patients might benefit from a complement-targeted therapy. Therapies directed against the complement system point to the necessity of a genetic workup of genes of complement components and regulators in patients with AAV. Genetic testing together with pluripotent stem cells and bioinformatics tools may broaden our approach to the treatment of patients with aggressive forms of AAV.

Endosomal ricin transport: involvement of Rab4- and Rab5-positive compartments.

Transport of the ribosome-inactivating protein ricin through endosomes was studied in A431 cells expressing Rab5-, Rab4-, and Rab11-GFP. It was shown that Rab5- and Rab4-positive functional domains of early endosomes are involved in ricin transport. Ricin enters cells by both clathrin-dependent and clathrin-independent mechanisms. The main pool of internalized toxin accumulates in early endosomes and remains associated with them for a long time. In contrast to earlier observations, current observations indicate that the majority of ricin avoids transport to lysosomes. The low level of ricin association with Rab11 as well as with transferrin accumulated in the pericentriolar recycling compartment shows that the compartment is not responsible for keeping ricin away from degradation in lysosomes. Escape from degradation in lysosomes is assumed to result from the potentiality of ricin to form assemblies within compartments.

Importance of Protocol Immunization in Epitope Selectivity of Monoclonal Antibodies Interacting with Binding Subunit of Viscumin.

The application of two immunization protocols and two screening systems has allowed to produce five hybridomas mlb5, mlb6, mlb7, mlb9 and Mbch1, secreting mAbs against different sites of viscumin B-subunit. On the base of mlb9 and Mbch1 hybridomas, the test-system has been developed, able to detect up to 5 ng/ml of viscumin and up to 1 ng/ml of its B-chain. Produced hybridomas and monoclonal antibodies will be used for the studies of intracellular transport of plant toxins. Monoclonal antibody mlb7 will be used for the studies of viscumin interactions with immune system of mammals.