Short-Term Mortality in Hospitalized Patients with Congestive Heart Failure: Markers of Thrombo-Inflammation Are Independent Risk Factors and Only Weakly Associated with Renal Insufficiency and Co-Morbidity Burden.

Congestive heart failure (CHF) is associated with significant morbidity and mortality. There has been renewed interest in using thrombo-inflammatory markers as prognostic tools in patients with CHF. To determine if thrombo-inflammatory markers are independent risk factors for 28-day mortality in hospitalized CHF patients, we retrospectively analyzed admission data extracted from 2008 consecutive patients admitted with a diagnosis of CHF to Zigong Fourth People's Hospital.

Interaction of the antiphospholipid syndrome autoantigen beta-2 glycoprotein I with DNA and neutrophil extracellular traps.

Beta-2 glycoprotein I (βGPI) is a phospholipid-binding plasma protein and prominent autoantigen in antiphospholipid syndrome (APS). Here, we tested the hypothesis that βGPI might bind to not only phospholipids, but also cell-free DNA and neutrophil extracellular traps (NETs). We report that βGPI interacts with cell-free DNA from different species, as well as NETs, in a dose-dependent manner, retarding their migration in an agarose-gel electrophoretic mobility shift assay.

Acute Kidney Injury Associated with Severe SARS-CoV-2 Infection: Risk Factors for Morbidity and Mortality and a Potential Benefit of Combined Therapy with Tocilizumab and Corticosteroids.

Background: Acute kidney injury (AKI) is a common complication in patients with severe COVID-19.

Methods: We retrospectively reviewed 249 patients admitted to an intensive care unit (ICU) during the first wave of the pandemic to determine risk factors for AKI. Demographics, comorbidities, and clinical and outcome variables were obtained from electronic medical records.

Predictors and clinical complications associated with antiphospholipid antibodies in sickle cell disease.

Although a higher prevalence of antiphospholipid autoantibodies (aPL) has been observed in some cohorts of sickle cell disease (SCD) patients, the clinical risk factors for the development of aPL and its associated complications remain unclear. In a retrospective study of 63 SCD patients, a lower hemoglobin concentration and higher white blood cell count were independently associated with an elevated aPL. SCD patients with elevated aPL had increased pregnancy complications (≥3 miscarriages, preterm delivery, pre-eclampsia) and venous thrombotic events.

A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial.

Background: Retrospective analysis of the transcriptomic host response in sepsis has demonstrated that sepsis can be separated into three endotypes-inflammatory (IE), adaptive (AE), and coagulopathic (CE), which have demonstrated prognostic significance. We undertook a prospective transcriptomic host response analysis in a subgroup of patients enrolled in the Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) trial.

Methods: Blood was obtained from 51 patients and profiled using a pre-established 33-mRNA classifier to determine sepsis endotypes.

Oral high dose vitamin B12 decreases renal superoxide and post-ischemia/reperfusion injury in mice.

Renal ischemia/reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), a potentially fatal syndrome characterized by a rapid decline in kidney function. Excess production of superoxide contributes to the injury. We hypothesized that oral administration of a high dose of vitamin B12 (B12 - cyanocobalamin), which possesses a superoxide scavenging function, would protect kidneys against IRI and provide a safe means of treatment.

Necroptotic cell binding of β -glycoprotein I provides a potential autoantigenic stimulus in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the development of autoantibodies against diverse self-antigens with damage to multiple organs. Immunization with the SLE autoantigen β -glycoprotein I (β GPI) and lipopolysaccharide (LPS), a known trigger of necroptosis, induces a murine model of SLE. We hypothesized that necroptotic cells, like apoptotic cells, provide a "scaffold" of cellular self-antigens, but, unlike apoptotic cells, necroptotic cells do so in a proinflammatory and immunogenic context.

Voices from the dead: The complex vocabulary and intricate grammar of dead cells.

Of the roughly one million cells per second dying throughout the body, the vast majority dies by apoptosis, the predominant form of regulated cell death in higher organisms. Long regarded as mere waste, apoptotic cells are now recognized as playing a prominent and active role in homeostatic maintenance, especially resolution of inflammation, and in the sculpting of tissues during development. The activities associated with apoptotic cells are continually expanding, with more recent studies demonstrating their ability to modulate such vital functions as proliferation, survival, differentiation, metabolism, migration, and angiogenesis.

AMPK-mediated activation of Akt protects renal tubular cells from stress-induced apoptosis in vitro and ameliorates ischemic AKI in vivo.

We have reported that preconditioning renal tubular cells (RTCs) with A-769662 [a pharmacological activator of AMP-activated protein kinase (AMPK)] reduces apoptosis of RTCs induced by subsequent stress and ameliorates the severity of ischemic acute kidney injury (AKI) in mice. In the present study, we examined the role of the phosphoinositide 3-kinase (PI3K)/Akt pathway in mediating these effects. Using shRNA, we developed knockdown (KD) RTCs to confirm that any novel effects of A-769662 are mediated specifically by AMPK.

Interactive and potentially independent roles of renin-angiotensin-aldosterone system blockade and the development of cardiorenal syndrome type 1 on in-hospital mortality among elderly patients admitted with acute decompensated congestive heart failure.

Purpose: Cardiorenal syndrome type 1 (CRS1), defined as worsening renal function from acute decompensated congestive heart failure (ADCHF), is complicated by the fact that CRS1 limits the use of common therapeutic strategies, such as angiotensin converting-enzyme inhibitors (ACEIs) or angiotensin II-receptor blockers (A2RB). The present study examines retrospectively the role of ACEI/A2RB usage on in-hospital mortality among elderly ADCHF patients, in particular those who developed CRS1.

Methods: We retrospectively examined the effects of ACEI/A2RB usage and CRS1 development (in-hospital change in serum creatinine ≥0.

β2-Glycoprotein I-Reactive T Cells in Autoimmune Disease.

Anti-phospholipid syndrome (APS) and systemic lupus erythematosus (SLE) are autoimmune diseases characterized by autoantibody production and autoantibody-related pathology. Anti-phospholipid antibodies (aPL) are found in all patients with APS and in 20-30% of individuals with SLE. aPL recognize a number of autoantigens, but the primary target in both APS and SLE is β2-glycoprotein I (β2GPI).

Repeated exposure of epithelial cells to apoptotic cells induces the specific selection of an adaptive phenotype: Implications for tumorigenesis.

The consequences of apoptosis extend beyond the mere death of the cell. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits PTEC proliferation, growth, and survival. Here, we tested the hypothesis that continual exposure to apoptotic targets can induce a phenotypic change in responding PTECs, as in other instances of natural selection.

T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein I.

Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipid-binding proteins, particularly β2-glycoprotein I.

Exploitation of Apoptotic Regulation in Cancer.

Within an organism, environmental stresses can trigger cell death, particularly apoptotic cell death. Apoptotic cells, themselves, are potent regulators of their cellular environment, involved primarily in effecting homeostatic control. Tumors, especially, exist in a dynamic balance of cell proliferation and cell death.

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death.

Cells dying by apoptosis, also referred to as regulated cell death, acquire multiple new activities that enable them to influence the function of adjacent live cells. Vital activities, such as survival, proliferation, growth, and differentiation, are among the many cellular functions modulated by apoptotic cells. The ability to recognize and respond to apoptotic cells appears to be a universal feature of all cells, regardless of lineage or organ of origination.

Preconditioning mice with activators of AMPK ameliorates ischemic acute kidney injury in vivo.

This study had two objectives: 1) to determine whether preconditioning cultured proximal tubular cells (PTCs) with pharmacological activators of AMP-activated protein kinase (AMPK) protects these cells from apoptosis induced by metabolic stress in vitro and 2) to assess the effects of preconditioning mice with these agents on the severity of ischemic acute renal kidney injury (AKI) in vivo. We demonstrate that preconditioning PTCs with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) or A-769662 reduces apoptosis of PTCs induced by subsequent stress. We also show that the reduction in cell death during metabolic stress associated with pretreatment by AMPK activators is associated with an increase in the cytosolic level of ATP, which is mediated by an increase in the rate of glycolysis.

Apoptotic cells activate AMP-activated protein kinase (AMPK) and inhibit epithelial cell growth without change in intracellular energy stores.

Apoptosis plays an indispensable role in the maintenance and development of tissues. We have shown that receptor-mediated recognition of apoptotic target cells by viable kidney proximal tubular epithelial cells (PTECs) inhibits the proliferation and survival of PTECs. Here, we examined the effect of apoptotic targets on PTEC cell growth (cell size during G1 phase of the cell cycle).

β2-Glycoprotein I-specific T cells are associated with epitope spread to lupus-related autoantibodies.

Systemic lupus erythematosus (SLE) is a prototypic model for B cell epitope spread in autoimmunity. Autoantibodies to numerous and molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting the apoptotic cell-binding protein β2-glycoprotein I (β2GPI).

Susceptibility to ATP depletion of primary proximal tubular cell cultures derived from mice lacking either the α1 or the α2 isoform of the catalytic domain of AMPK.

Background: The purpose of this study was to determine whether AMPK influences the survival of primary cultures of mouse proximal tubular (MPT) cells subjected to metabolic stress. Previous studies, using an immortalized MPT cell line, suggest that AMPK is activated during metabolic stress, and ameliorates stress-induced apoptosis of these cells.

Methods: Primary MPT cells were cultured from AMPK knockout (KO) mice lacking either the α1 or the α2 isoform of the catalytic domain of AMPK.

Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction.

Background: Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs.

Mammalian target of rapamycin and the kidney. II. Pathophysiology and therapeutic implications.

The mTOR pathway plays an important role in a number of common renal diseases, including acute kidney injury (AKI), diabetic nephropathy (DN), and polycystic kidney diseases (PKD). The activity of mTOR complex 1 (mTORC1) is necessary for renal regeneration and repair after AKI, and inhibition of mTORC1 by rapamycin has been shown to delay recovery from ischemic AKI in animal studies, and to prolong delayed graft function in humans who have received a kidney transplant. For this reason, administration of rapamycin should be delayed or discontinued in patients with AKI until full recovery of renal function has occurred.

Mammalian target of rapamycin and the kidney. I. The signaling pathway.

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a fundamental role in regulating cellular homeostasis and metabolism. In a two-part review, we examine the complex molecular events involved in the regulation and downstream effects of mTOR, as well as the pivotal role played by this kinase in many renal diseases, particularly acute kidney injury, diabetic nephropathy, and polycystic kidney diseases. Here, in the first part of the review, we provide an overview of the complex signaling events and pathways governing mTOR activity and action.

Recognition-dependent signaling events in response to apoptotic targets inhibit epithelial cell viability by multiple mechanisms: implications for non-immune tissue homeostasis.

Apoptosis allows for the removal of damaged, aged, and/or excess cells without harm to surrounding tissue. To accomplish this, cells undergoing apoptosis acquire new activities that enable them to modulate the fate and function of nearby cells. We have shown that receptor-mediated recognition of apoptotic versus necrotic target cells by viable kidney proximal tubular epithelial cells (PTEC) modulates the activity of several signaling pathways critically involved in regulation of proliferation and survival.