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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. Results: Univariate analysis revealed older age, higher admission serum creatinine, elevated Sequential Organ Failure Assessment (SOFA) score, elevated admission D-Dimer, elevated CRP on day 2, mechanical ventilation, vasopressor requirement, and azithromycin usage as significant risk factors for AKI. Multivariate analysis demonstrated that higher admission creatinine (p = 0.0001, OR = 2.41, 95% CI = 1.56–3.70), vasopressor requirement (p = 0.0001, OR = 3.20, 95% CI = 1.69–5.98), elevated admission D-Dimer (p = 0.008, OR = 1.0001, 95% CI = 1.000–1.001), and elevated C-reactive protein (CRP) on day 2 (p = 0.033, OR = 1.0001, 95% CI = 1.004–1.009) were independent risk factors. Conversely, the combined use of Tocilizumab and corticosteroids was independently associated with reduced AKI risk (p = 0.0009, OR = 0.437, 95% CI = 0.23–0.81). Conclusion: This study confirms the high rate of AKI and associated mortality among COVID-19 patients admitted to ICUs and suggests a role for inflammation and/or coagulopathy in AKI development. One should consider the possibility that early administration of anti-inflammatory agents, as is now routinely conducted in the management of COVID-19-associated acute respiratory distress syndrome, may improve clinical outcomes in patients with AKI. [ABSTRACT FROM AUTHOR]

We report an approximate energy distribution (coarse spectrum) over the range ~0.1 to > 10 keV for the X-ray output of an argon Z-pinch. The tests, conducted at ~15-MA peak current, utilized an 8-cm diameter double-shell nozzle. Sze et al. (2001) have previously described the performance of this Z-pinch with emphasis on the K-shell line emission at ~3 keV. Additional measurements that address the non-K-line output of the Z-pinches are presented here. On the one hand, > 4-keV photons due to the free-bound continuum constitute a significant fraction, almost 30%, of the nominal K-shell emission. On the other hand, the sub-3-keV L-shell lines and continuum show distinctive time histories and significant yields. These nonresonance-line emissions are important for a more complete understanding of the implosion physics, for proper analysis of diagnostic responses, and for their effects upon objects exposed to the Z-pinch's radiation. Index Terms--X-ray diagnostics, X-ray spectra, Z-pinches.

We have developed a 12-cm-diameter Ar gas Z-pinch load, which produces two annular gas shells and a center gas jet. The two-dimensional (2-D) gas density profiles of the load, in r-[theta]and r-z planes, were measured with submillimeter spatial resolutions using the planar-laser-induced fluorescence (PLIF) method, for conditions used in Z-pinch experiments. Due to interactions between the shells, the net gas density profile differs from the superposition of the individual shell profiles. Narrow density peaks are observed both at smaller and larger radii than the radius where the shells come in contact with each other. Two-dimensional flow velocity distributions are determined from the displacements between the fluorescence and later time phosphorescence images. The measured stream velocities of argon gas puffs are 650 [+ or -] 20 m/s, higher than the ideal gas velocity due to the formation of clusters in the supersonic gas flow. Indeed, clusters were observed in earlier Rayleigh scattering experiments. The gas measurements of the initial phase using the PLIF will be combined with other density measurements of the implosion and pinch phases to better understand the implosion dynamics and to provide initial conditions for simulation codes. Index Terms--Argon gas puff, laser-induced fluorescence, plasma radiation source, Z-pinch.

Mouse proximal tubular cells (BUMPT), when cultured in the absence of growth factors, activate a default apoptotic pathway. Although Wnt signaling antagonizes the effect of proapoptotic triggers, its role in regulating the default pathway of apoptosis is less well defined. The present study examines the hypothesis that lithium ([Li.sup.+]) and (2'Z,3'E)-6-bromoindirubin-3'-oxime (BIO), two glycogen synthase kinase-3[beta] (GSK3[beta]) inhibitors, promote survival of growth factor-deprived renal epithelial cells by activating the Wnt pathway. These studies demonstrate that [Li.sup.+] and BIO activate Wnt signaling as indicated by the following changes: phosphorylation (inhibition) of GSK3[beta]; decreased phosphorylation of [beta]-catenin (a GSK3[beta] substrate); nuclear translocation of [beta]-catenin; specific transcriptional activation of Tcf/catenin-responsive pTopflash constructs; and an increase in the expression of cyclin D1 (indicative of a promitogenic cell response). In addition, [Li.sup.+] or BIO significantly increases the phosphorylation (activation) of Akt, an anti-apoptotic protein, and inhibits apoptosis (decreases both annexin-V staining and caspase-3 activation), during serum deprivation. Inhibition of phosphatidylinositol 3-kinase (responsible for Akt activation) either by wortmanin or LY-294002 prevented [Li.sup.+]-or BIO-induced Akt phosphorylation and reduces cell survival without altering the phosphorylation state of GSK3[beta]. [Li.sup.+] or BIO also increases the expression of insulin-like growth factor-II (IGF-II), a potent proliferative signaling protein. [Li.sup.+] or BIO-free conditioned medium harvested from [Li.sup.+] or BIO-exposed cells also induced Akt phosphorylafion, mimicking the protective effect of the two GSK3[beta] inhibitors on serum-starved cells. Furthermore, the effect of conditioned medium on Akt phosphorylation could be inhibited by either LY-294002 or IGF-binding protein. BIO, a specific GSK3[beta] inhibitor, replicated the protective effect of [Li.sup.+] on cell viability, suggesting that GSK3[beta] activation is important for initiating the apoptotic pathway. Taken together, these data suggest that [Li.sup.+] or BIO promotes renal epithelial cell survival by inhibiting apoptosis through GSK3[beta]-dependent activation of the Wnt pathway and subsequent release of IGF-II. Extracellular IGF-II serves as an autocrine survival factor that is responsible, in part, for activating the anti-apoptotic phosphatidylinositol-3-kinase-Akt pathway during serum deprivation. serum deprivation; renal epithelial cells; insulin-like growth factors; [beta]-catenin; glycogen synthase kinase-3[beta]; apoptosis

Abstract Background Acute kidney injury (AKI) occurs commonly in the setting of orthotopic liver transplantation (OLT). To date, the correlation between AKI post-OLT and pre-operative changes in renal function has not been rigorously examined. Methods To determine the impact of pre-OLT changes in renal function on AKI post-OLT, as well as to identify risk factors for AKI, we analyzed the prospectively maintained NIDDK Liver Transplantation Database, which includes patients who received their first OLT between April 15, 1990, and June 30, 1994. We used the AKI Network definition of AKI. Results Surprisingly, univariate analysis revealed that worsening renal function while awaiting OLT was protective to the development of AKI post-OLT. Independent predictors of AKI were increased body mass index, increased Childs-Pugh-Turcott score, decreased urine output during cross-clamp, improved renal function while awaiting OLT, increased post-operative stroke volume, non-Caucasian race, and post-operative use of tacrolimus. Conclusions The correlation between improving renal function pre-OLT and AKI post-OLT may represent true protection (via ischemic pre-conditioning) or, alternatively, a masking of milder forms of AKI (via improved renal perfusion through correction of the cirrhotic milieu). These results highlight the complex interaction between liver and kidney disease, and suggest that not only the etiology but also the course of pre-OLT renal dysfunction may be a critical determinant of renal function post-OLT.

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 β2‐glycoprotein I (β2GPI) 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. We demonstrate that β2GPI indeed binds to necroptotic cells and serves as a target for anti‐β2GPI autoantibodies. We further demonstrate that necroptotic, but not apoptotic, cells promote antigenic presentation of β2GPI to CD4 T cells by dendritic cells. Finally, we show that β2GPI/LPS‐immunized mice deficient in RIPK3 (receptor‐interacting serine/threonine‐protein kinase 3) or MLKL (mixed lineage kinase domain like), and consequently unable to undergo necroptosis, have reduced SLE autoantibody production and pathology. RIPK3−/− mice had low levels of SLE autoantibodies and no renal pathology, while MLKL−/− mice produced low levels of SLE autoantibodies initially, but later developed levels comparable with wild type (WT) mice and pathology intermediate to that of WT and RIPK3−/− mice. Serum cytokine levels induced by LPS tended to be lower in RIPK3−/− and MLKL−/− mice than in WT mice, suggesting that impaired proinflammatory cytokine production may impact the initiation of autoantibody production in both strains. Our data suggest that self‐antigen (i.e. β2GPI) presented in the context of necroptosis and proinflammatory signals may be sufficient to overcome immune tolerance and induce SLE. [ABSTRACT FROM AUTHOR]

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. We reduced expression of the total β-domain of AMPK in KD RTCs by >80%. Control RTCs were transfected with "scrambled" shRNA. Preconditioning control RTCs with A-769662 increased both the phosphorylation (activity) of AMPK and survival of these cells when exposed to subsequent stress, but neither effect was observed in KD cells. These data demonstrate that activation of AMPK by A-769662 is profoundly impaired in KD cells. A-769662 activated PI3K and Akt in control but not KD RTCs. These data provide novel evidence that activation of the PI3K/Akt pathway by A-769662 is mediated specifically through activation of AMPK and not by a nonspecific mechanism. We also demonstrate that, in control RTCs, Akt plays a role in mediating the antiapoptotic effects of A-769662. In addition, we provide evidence that AMPK ameliorates the severity of ischemic AKI in mice and that this effect is also partially mediated by Akt. Finally, we provide evidence that AMPK activates PI3K by inhibiting mechanistic target of rapamycin complex 1 and preventing mechanistic target of rapamycin complex 1-mediated inhibition of insulin receptor substrate-1-associated activation of PI3K. [ABSTRACT FROM AUTHOR]

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 ≥0.3 mg/dL or ≥0.5 mg/dL), as well as their potential interaction, on in-hospital mortality among elderly ADCHF patients (aged ≥65 years). Employing univariate and multivariate analyses, we performed risk-factor analysis on a cohort of 419 patients (51 nonsurvivors [12.2%]) for whom we had complete clinical and laboratory data (median follow-up 5 days) from 2,361 consecutive elderly ADCHF patients (106 nonsurvivors [4.6%]). Results: By multivariate analysis, the two strongest independent predictors of in-hospital mortality were CRS1 development (OR 7.8, 95% CI 3.9–15.5; P=0.00001) and lack of ACEI/A2RB usage (OR 0.49, CI 0.25–0.93; P=0.043). The effect of CRS1 was graded, with increasing CRS1 severity associated with increased mortality. On multivariate subgroup analysis, the association between lack of ACEI/A2RB usage and increased mortality remained a significant independent predictor among patients not developing CRS1 (OR 0.24, CI 0.083–0.721; P=0.011). Conclusion: Our data suggest that development of CRS1 and lack of ACEI/A2RB usage are statistically independent predictors of in-hospital mortality for elderly ADCHF patients, with CRS1 being the stronger of the two risk factors. While it remains unclear whether lack of ACEI/A2RB usage is causally related to increased mortality or reflects another risk factor inducing physicians to forego ACEIs/A2RBs, our findings nevertheless indicate the need to address this issue in future prospective studies. [ABSTRACT FROM AUTHOR]

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. This special feature of the tumorous microenvironment--namely, the prominence and persistence of cell death--necessarily entails a magnification of the extrinsic, postmortem effects of dead cells. In both normal and malignant tissues, apoptotic regulation is exerted through immune as well as non-immune mechanisms. Apoptotic cells suppress the repertoire of immune reactivities, both by attenuating innate (especially inflammatory) responses and by abrogating adaptive responses. In addition, apoptotic cells modulate multiple vital cell activities, including survival, proliferation (cell number), and growth (cell size). While the microenvironment of the tumor may contribute to apoptosis, the postmortem effects of apoptotic cells feature prominently in the reciprocal acclimatization between the tumor and its environment. In much the same way that pathogens evade the host's defenses through exploitation of key aspects of innate and adaptive immunity, cancer cells subvert several normal homeostatic processes, in particular wound healing and organ regeneration, to transform and overtake their environment. In understanding this subversion, it is crucial to view a tumor not simply as a clone of malignant cells, but rather as a complex and highly organized structure in which there exists a multidirectional flow of information between the cancer cells themselves and the multiple other cell types and extracellular matrix components of which the tumor is comprised. Apoptotic cells, therefore, have the unfortunate consequence of facilitating tumorigenesis and tumor survival. [ABSTRACT FROM AUTHOR]

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. In addition, we provide evidence that the effect of AMPK activators on glycolysis is mediated, at least in part, by an increased uptake of glucose, and by the induction of hexokinase II (HK II) expression. Our data also show that the increased in HK II expression associated with preconditioning with AMPK activators is mediated by the activation (phosphorylation) of the cAMP-response element binding protein (CREB). We also provide entirely novel evidence that that A-79662 is substantially more effective than AICAR in mediating these alterations in PTCs in vitro. Finally, we demonstrate that preconditioning mice with AICAR or A-769662 substantially reduces the severity of renal dysfunction and tubular injury in a model of ischemic AKI in vivo and that the efficacy of AICAR and A-768662 in ameliorating ischemic AKI in vivo is comparable. [ABSTRACT FROM AUTHOR]