Predicting Kidney Failure, Cardiovascular Disease and Death in Advanced CKD Patients.

Introduction: Predicting the timing and occurrence of kidney replacement therapy (KRT), cardiovascular events, and death among patients with advanced chronic kidney disease (CKD) is clinically useful and relevant. We aimed to externally validate a recently developed CKD G4+ risk calculator for these outcomes and to assess its potential clinical impact in guiding vascular access placement. Methods: We included 1517 patients from the European Quality (EQUAL) study, a European multicentre prospective cohort study of nephrology-referred advanced CKD patients aged ≥65 years. Model performance was assessed based on discrimination and calibration. Potential clinical utility for timing of referral for vascular access placement was studied with diagnostic measures and decision curve analysis (DCA). Results: The model showed a good discrimination for KRT and "death after KRT," with 2-year concordance (C) statistics of 0.74 and 0.76, respectively. Discrimination for cardiovascular events (2-year C-statistic: 0.70) and overall death (2-year C-statistic: 0.61) was poorer. Calibration was fairly accurate. Decision curves illustrated that using the model to guide vascular access referral would generally lead to less unused arteriovenous fistulas (AVFs) than following estimated glomerular filtration rate (eGFR) thresholds. Conclusion: This study shows moderate to good predictive performance of the model in an older cohort of nephrology-referred patients with advanced CKD. Using the model to guide referral for vascular access placement has potential in combating unnecessary vascular surgeries.

'Mali Matters': reflections on a leadership and quality improvement project to improve blood transfusion safety at Maluti Adventist Hospital, Mapoteng, Lesotho.

INTRODUCTION: This report outlines a quality improvement (QI) project aiming to improve blood transfusion safety at Maluti Adventist Hospital (MAH), Lesotho, from August 2019 to January 2020.The project team comprised nine local staff members and two UK doctors working through the NHS 'Improving Global Health through Leadership Development' (IGH) programme. METHODS: Baseline data was gathered and a 'process mapping' meeting held to understand existing processes and identify methods for improvement.Improvements were implemented using Plan-Do-Study-Act (PDSA) methodology.The NHS Healthcare Leadership Model was used as a framework for leadership development and team members reflected on their personal learning. RESULTS: Varied interventions included introduction of a pre-transfusion bedside safety checklist and staff training.Documentation of critical patient identifiers for transfusion improved. Completion of the bedside safety checklist was 65.5% by 3 months. Knowledge scores improved post-transfusion training. 77% of staff strongly agreed and 21% agreed that the training was useful.Challenges and further work were reflected on. DISCUSSION: This collaborative system-strengthening project provided varied, reciprocal learning experiences including skills in leadership, teamwork, teaching, QI methodology, communication and IT.Our experiences will help to inform ongoing work at MAH and may be helpful to others conducting similar work in related settings.

Non-infectious aortitis in an immunosuppressed renal transplant recipient with IgA nephropathy.

A 54-year-old woman presented with atypical chest pain, fever and malaise. She was immunosuppressed with three agents following a living-donor kidney transplant 1 year previously. Her native kidney failure was secondary to biopsy-demonstrated crescentic IgA nephropathy, with systemic involvement. A CT pulmonary angiogram revealed an inflammatory cuff of soft tissue around the descending thoracic aorta suggesting aortitis. Inflammatory markers were elevated. Given her immunosuppression, the patient was screened extensively for infective causes and was empirically commenced on intravenous meropenem. After 72 hours of no clinical or serological response to antibiotic therapy, negative microbiological investigations and worsening inflammation on serial imaging, she was commenced on high-dose methylprednisolone for presumed inflammatory aortitis. Symptoms and inflammatory markers rapidly normalisedand the patient was discharged home on oral prednisolone. A clinical diagnosis of IgA-related aortitis was made. Imaging 3 months later showed complete resolution of the aortitis.

NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing.

A cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca(2+)-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from the endoplasmic reticulum activates the store-operated Ca(2+)-influx pathway that is necessary for exocytosis, it is not a sufficient stimulus. Here we identify the Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs), as being important for T cell receptor signaling in CTLs. We demonstrate that cytolytic granules are not only reservoirs of cytolytic proteins but are also the acidic Ca(2+) stores mobilized by NAADP via TPC channels on the granules themselves, so that TPCs migrate to the immunological synapse upon CTL activation. Moreover, NAADP activates TPCs to drive exocytosis in a way that is not mimicked by global Ca(2+) signals induced by IP(3) or ionomycin, suggesting that critical, local Ca(2+) nanodomains around TPCs stimulate granule exocytosis. Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca(2+) signals that lead to their own exocytosis and to cell killing. This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell function and may impact on stimulus-secretion coupling in wider cellular contexts.