5 research outputs found

    Global epidemiology and outcomes of acute kidney injury

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    Acute kidney injury (AKI) is a commonly encountered syndrome associated with various aetiologies and pathophysiological processes leading to decreased kidney function. In addition to retention of waste products, impaired electrolyte homeostasis and altered drug concentrations, AKI induces a generalized inflammatory response that affects distant organs. Full recovery of kidney function is uncommon, which leaves these patients at risk of long-term morbidity and death. Estimates of AKI prevalence range from <1% to 66%. These variations can be explained by not only population differences but also inconsistent use of standardized AKI classification criteria. The aetiology and incidence of AKI also differ between high-income and low-to-middle-income countries. High-income countries show a lower incidence of AKI than do low-to-middle-income countries, where contaminated water and endemic diseases such as malaria contribute to a high burden of AKI. Outcomes of AKI are similar to or more severe than those of patients in high-income countries. In all resource settings, suboptimal early recognition and care of patients with AKI impede their recovery and lead to high mortality, which highlights unmet needs for improved detection and diagnosis of AKI and for efforts to improve care for these patients

    Global epidemiology and outcomes of acute kidney injury

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    Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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    BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old
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