Acute kidney injury (AKI) has been reported in up to 25% of critically-ill patients with SARS-CoV-2 infection, especially in those with underlying comorbidities. AKI is associated with high mortality ...rates in this setting, especially when renal replacement therapy is required. Several studies have highlighted changes in urinary sediment, including proteinuria and hematuria, and evidence of urinary SARS-CoV-2 excretion, suggesting the presence of a renal reservoir for the virus. The pathophysiology of COVID-19 associated AKI could be related to unspecific mechanisms but also to COVID-specific mechanisms such as direct cellular injury resulting from viral entry through the receptor (ACE2) which is highly expressed in the kidney, an imbalanced renin–angotensin–aldosteron system, pro-inflammatory cytokines elicited by the viral infection and thrombotic events. Non-specific mechanisms include haemodynamic alterations, right heart failure, high levels of PEEP in patients requiring mechanical ventilation, hypovolemia, administration of nephrotoxic drugs and nosocomial sepsis. To date, there is no specific treatment for COVID-19 induced AKI. A number of investigational agents are being explored for antiviral/immunomodulatory treatment of COVID-19 and their impact on AKI is still unknown. Indications, timing and modalities of renal replacement therapy currently rely on non-specific data focusing on patients with sepsis. Further studies focusing on AKI in COVID-19 patients are urgently warranted in order to predict the risk of AKI, to identify the exact mechanisms of renal injury and to suggest targeted interventions.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
In severe SARS-CoV-2 infections, emerging data including recent histopathological studies have emphasized the crucial role of endothelial cells (ECs) in vascular dysfunction, immunothrombosis, and ...inflammation.Histopathological studies have evidenced direct viral infection of ECs, endotheliitis with diffuse endothelial inflammation, and micro- and macrovascular thrombosis both in the venous and arterial circulations. Venous thrombotic events, particularly pulmonary embolism, with elevated D-dimer and coagulation activation are highly prevalent in COVID-19 patients. The pro-inflammatory cytokine storm, with elevated levels of interleukin-6 (IL-6), IL-2 receptor, and tumor necrosis factor-α, could also participate in endothelial dysfunction and leukocyte recruitment in the microvasculature. COVID-19-induced endotheliitis may explain the systemic impaired microcirculatory function in different organs in COVID-19 patients. Ongoing trials directly and indirectly target COVID-19-related endothelial dysfunctions: i.e., a virus-cell entry using recombinant angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS-2) blockade, coagulation activation, and immunomodulatory therapies, such as anti-IL-6 strategies. Studies focusing on endothelial dysfunction in COVID-19 patients are warranted as to decipher their precise role in severe SARS-CoV-2 infection and organ dysfunction and to identify targets for further interventions.
Background
Acute Kidney Injury (AKI) is a frequent complication of severe SARS-CoV-2 infection. Multiple mechanisms are involved in COVID-19-associated AKI, from direct viral infection and secondary ...inflammation to complement activation and microthrombosis. However, data are limited in critically-ill patients. In this study, we sought to describe the prevalence, risk factors and prognostic impact of AKI in this setting.
Methods
Retrospective monocenter study including adult patients with laboratory confirmed SARS-CoV-2 infection admitted to the ICU of our university Hospital. AKI was defined according to both urinary output and creatinine KDIGO criteria.
Results
Overall, 100 COVID-19 patients were admitted. AKI occurred in 81 patients (81%), including 44, 10 and 27 patients with AKI stage 1, 2 and 3 respectively. The severity of AKI was associated with mortality at day 28 (
p
= 0.013). Before adjustment, the third fraction of complement (C3), interleukin-6 (IL-6) and ferritin levels were higher in AKI patients. After adjustment for confounders, both severity (modified SOFA score per point) and AKI were associated with outcome. When forced in the final model, C3 (OR per log 0.25; 95% CI 0.01–4.66), IL-6 (OR per log 0.83; 95% CI 0.51–1.34), or ferritin (OR per log 1.63; 95% CI 0.84–3.32) were not associated with AKI and did not change the model.
Conclusion
In conclusion, we did not find any association between complement activation or inflammatory markers and AKI. Proportion of patients with AKI during severe SARS-CoV-2 infection is higher than previously reported and associated with outcome.
The renal microvasculature is emerging as a key player in acute and chronic kidney diseases. Renal microvascular disease involves alterations in endothelial barrier permeability, exaggerated ...inflammation, impairment of endothelium-dependent vasorelaxation involving the nitric oxide system, increased oxidative stress, and loss of angiogenic factors. Moreover, evidence suggests that there is a microvascular component to the pathogenesis of renal scarring. New technology is being developed to explore renal microcirculation in vivo in experimental models and humans. This technology will provide a better understanding of the pathogenesis of kidney diseases and will help guide specific therapeutic strategies aimed at restoring the renal microcirculation. This article reviews the cellular and molecular mechanisms of renal microvascular dysfunction in acute and chronic kidney diseases and the potential diagnostic and therapeutic implications of these findings. Recent developments in the monitoring of renal microcirculation are described with respect to their advantages and limitations, and future directions are outlined.
Purpose
Coronavirus disease 2019 (COVID-19) is creating an unprecedented healthcare crisis. Understanding the determinants of mortality is crucial to optimise intensive care unit (ICU) resource use ...and to identify targets for improving survival.
Methods
In a multicentre retrospective study, we included 379 COVID-19 patients admitted to four ICUs between 20 February and 24 April 2020 and categorised according to time from disease onset to ICU admission. A Cox proportional-hazards model identified factors associated with 28-day mortality.
Results
Median age was 66 years (53–68) and 292 (77%) were men. The main comorbidities included obesity and overweight (67%), hypertension (49.6%) and diabetes (30.1%). Median time from disease onset (i.e., viral symptoms) to ICU admission was 8 (6–11) days (missing for three); 161 (42.5%) patients were admitted within a week of disease onset, 173 (45.6%) between 8 and 14 days, and 42 (11.1%) > 14 days after disease onset; day 28 mortality was 26.4% (22–31) and decreased as time from disease onset to ICU admission increased, from 37 to 21% and 12%, respectively. Patients admitted within the first week had higher SOFA scores, more often had thrombocytopenia or acute kidney injury, had more limited radiographic involvement, and had significantly higher blood IL-6 levels. Age, COPD, immunocompromised status, time from disease onset, troponin concentration, and acute kidney injury were independently associated with mortality.
Conclusion
The excess mortality in patients admitted within a week of disease onset reflected greater non-respiratory severity. Therapeutic interventions against SARS-CoV-2 might impact different clinical endpoints according to time since disease onset.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Severe inflammatory diseases, including sepsis, are characterized by an impaired host adaptive and innate immunity which results in immunosuppression, responsible for secondary infections and ...increased morbidity and mortality in critically ill patients. T cells are major actors of the immune system. During post-aggressive immunosuppression, lymphopenia, reduction of innate T cells, changes in T helper cell polarization and regulatory T cell increase are observed. The main mechanisms involved in T cell dysregulation are T cell apoptosis, autophagy deficiency, T cell anergy, T cell exhaustion and T cell metabolic reprogramming. In this review, we describe the alterations of T cell regulation, their mechanisms, and their association with clinical outcomes in severe inflammatory diseases, foremost of which is the sepsis.
Take home message
This review focuses on the alterations of T cell regulation and their mechanisms in severe inflammatory ICU diseases. Lymphopenia, reduction of innate T cells, changes in T helper cell polarization and regulatory T cell increase contribute to secondary immunosuppression in ICU patients.
Background
Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role of substrate utilization and mitochondrial ...dysfunction in the pathophysiology of sepsis-related organ dysfunction. The purpose of this review is to present this evidence as a coherent whole and to highlight future research directions.
Main text
Sepsis is characterized by systemic and organ-specific changes in metabolism. Alterations of oxygen consumption, increased levels of circulating substrates, impaired glucose and lipid oxidation, and mitochondrial dysfunction are all associated with organ dysfunction and poor outcomes in both animal models and patients. The pathophysiological relevance of bioenergetics and metabolism in the specific examples of sepsis-related immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury and diaphragmatic failure is also described.
Conclusions
Recent understandings in substrate utilization and mitochondrial dysfunction may pave the way for new diagnostic and therapeutic approaches. These findings could help physicians to identify distinct subgroups of sepsis and to develop personalized treatment strategies. Implications for their use as bioenergetic targets to identify metabolism- and mitochondria-targeted treatments need to be evaluated in future studies.
Thrombotic thrombocytopenic purpura (TTP) is a multiorgan disorder. Organ dysfunction occurs as a consequence of widespread microvascular thrombosis, especially in the heart, brain and kidney, ...causing transient or partial occlusion of vessels, resulting in organ ischemia. Intensive care unit (ICU) admission varies between 40% and 100% of patients with TTP, either because of severe organ failure or in order to initiate emergency plasma exchange (PEx). Severe neurologic manifestations and cardiac involvement have been associated with higher mortality. Acute kidney injury, although usually less severe than that in hemolytic and uremic syndrome, is common during TTP. Initial management in the ICU should always be considered in TTP patients. The current treatment of TTP in the acute phase is based on urgent PEx, combined with corticosteroid therapy, B-cell-targeted immunotherapy, rituximab and inhibition of the interaction between ultra-large Von Willebrand factor multimers and platelets, using caplacizumab, a monoclonal antibody. ICU management permits close monitoring and the rapid introduction of life-sustaining therapies. This review details the epidemiology of TTP in the ICU, organ failures of critically ill patients with TTP, and the initial management of TTP patients in the ICU.
Cancer immunotherapy has now entered clinical practice and has reshaped the standard of care for many cancer patients. With these new strategies, specific toxicities have emerged, and renal side ...effects have been described. In this review, we will describe the causes of acute kidney injury in CAR T cell, immune checkpoint inhibitors and other cancer immuno-therapy recipients. CAR T cell therapy and bispecific T cell engaging antibodies can lead to acute kidney injury as a consequence of cytokine release syndrome, tumor lysis syndrome, sepsis or specific CAR T cell infiltration. Immune checkpoint blockade most often results in acute tubular interstitial nephritis, but glomerular diseases have also been described. Although the pathophysiology remains mostly elusive, we will describe the mechanisms of renal damage in these contexts, its prognosis and treatment. As the place of immunotherapy in the anti-cancer armamentarium is exponentially increasing, close collaboration between nephrologists and oncologists is of utmost importance to provide the best standard of care for these patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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