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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In sepsis-induced acute renal failure, actin cytoskeletal alterations result in shedding of proximal tubule epithelial cells (PTEC) and tubular obstruction. This study examined the hypothesis that inflammatory cytokines, released early in sepsis, cause PTEC cytoskeletal damage and alter integrin-dependent cell-matrix adhesion. The question of whether the intermediate nitric oxide (NO) modulates these cytokine effects was also examined. After exposure of human PTEC to tumor necrosis factor-alpha, interleukin-1 alpha, and interferon-gamma, the actin cytoskeleton was disrupted and cells became elongated, with extension of long filopodial processes. Cytokines induced shedding of viable, apoptotic, and necrotic PTEC, which was dependent on NO synthesized by inducible NO synthase (iNOS) produced as a result of cytokine actions on PTEC. Basolateral exposure of polarized PTEC monolayers to cytokines induced maximal NO-dependent cell shedding, mediated in part through NO effects on cGMP. Cell shedding was accompanied by dispersal of basolateral beta(1) integrins and E-cadherin, with corresponding upregulation of integrin expression in clusters of cells elevated above the epithelial monolayer. These cells demonstrated coexpression of iNOS and apically redistributed beta(1) integrins. Attachment studies demonstrated that the major ligand involved in cell anchorage was laminin, probably through interactions with the integrin alpha(3)beta(1). This interaction was downregulated by cytokines but was not dependent on NO. These studies provide a mechanism by which inflammatory cytokines induce PTEC damage in sepsis, in the absence of hypotension and ischemia. Future therapeutic strategies aimed at specific iNOS inhibition might inhibit PTEC shedding after cytokine-induced injury and delay the onset of acute renal failure in sepsis.
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PMID:Coexpressed nitric oxide synthase and apical beta(1) integrins influence tubule cell adhesion after cytokine-induced injury. 1167 13

The mortality from sepsis complicated by renal failure remains extremely high despite the application of modern renal replacement therapy. This study investigated whether treatment with a bioartificial kidney consisting of a hemofilter in a continuous venovenous hemofiltration circuit (CVVH) with a cartridge containing renal proximal tubule cells, also called the Renal Tubule Assist Device (RAD), would alter the course of sepsis in an animal model. The RAD has been previously characterized in vitro and ex vivo and provides transport, metabolic and endocrine activity. Mongrel dogs (n = 10) underwent surgical nephrectomy and 48 h later were treated with CVVH and either a RAD containing cells (n = 5) or an identically prepared sham cartridge (n = 5). After 4 h of therapy, intravenous endotoxin 2 mg/kg was infused over 1 h to simulate gram-negative septic shock. Data on blood pressure, cardiac output and systemic markers of inflammation were collected. Mean peak levels of an anti- inflammatory cytokine, IL-10, were significantly higher in cell-treated animals (15.25 vs. 6.29 ng/ml; p = 0.037), and mean arterial pressures were higher in cell-treated versus sham-treated animals (p < 0.04). We have demonstrated that treatment of an animal model of endotoxin shock and renal failure with a bioartificial kidney has measurable effects on circulating mediators of inflammation and on hemodynamic stability of the challenged animal.
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PMID:Bioartificial kidney alters cytokine response and hemodynamics in endotoxin-challenged uremic animals. 1180 60

The bioartificial kidney (BAK) consists of a conventional hemofiltration cartridge in series with a renal tubule assist device (RAD) containing 10(9) porcine renal proximal tubule cells. BAK replaces filtration, transport, and metabolic and endocrinologic activities of a kidney. Previous work in an acutely uremic dog model demonstrated that BAK ameliorated endotoxin (lipopolysaccharide [LPS])-induced hypotension and altered plasma cytokine levels. To further assess the role of BAK in sepsis in acute renal failure, dogs were nephrectomized and 48 h later administered intraperitoneally with 30 x 10(10) bacteria/kg of E. coli. One hour after bacterial administration, animals were placed in a continuous venovenous hemofiltration circuit with either a sham RAD without cells (n = 6) or a RAD with cells (n = 6). BP, cardiac output, heart rate, pulmonary capillary wedge pressure, and systemic vascular resistance were measured throughout the study. All animals tested were in renal failure, with blood urea nitrogen and serum creatinine concentrations greater than 60 and 6 mg/dl, respectively. RAD treatment maintained significantly better cardiovascular performance, as determined by arterial BP (P < 0.05) and cardiac output (P < 0.02), for longer periods than sham RAD therapy. Consistently, all sham RAD-treated animals, except one, expired within 2 to 9 h after bacterial administration, whereas all RAD-treated animals survived more than 10 h. Plasma levels of TNF-alpha, IL-10, and C-reactive protein (CRP) were measured during cell RAD and sham RAD treatment. IL-10 levels were significantly higher (P < 0.01) during the entire treatment interval in the RAD animals compared with sham controls. These data demonstrated in a pilot large animal experiment that the BAK with RAD altered plasma cytokine levels in acutely uremic animals with septic shock. This change was associated with improved cardiovascular performance and increased survival time. These results demonstrate that the addition of cell therapy to hemofiltration in an acutely uremic animal model with septic shock ameliorates cardiovascular dysfunction, alters systemic cytokine balance, and improves survival time.
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PMID:Bioartificial kidney ameliorates gram-negative bacteria-induced septic shock in uremic animals. 1253 47

The kidney is unique in that it is the first organ for which long-term ex vivo substitutive therapy has been available. The first hemodialyzer was successfully applied to a human patient with acute renal failure in 1948, and the first successful allograft transplantation was performed with a kidney in 1951. Both treatments are used today. There is ample evidence that the small solute clearance function provided by hemodialysis does not confer the same survival advantage as a functional kidney, both in acute and in chronic renal failure. To mimic the metabolic, endocrine, and immunologic functions of the kidney, our group has successfully engineered a bioartificial device that includes a conventional dialysis filter and a bioreactor containing 10(9) renal proximal tubule cells. We have demonstrated differentiated activity of these cells both in vitro and ex vivo in a large animal model. The bioreactor has been shown to confer a survival advantage in two large animal models of gram-negative sepsis, seemingly due to modulation of inflammatory mediators. This bioartificial kidney has now completed a Phase I clinical trial in acute renal failure.
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PMID:Cell therapy of renal failure. 1469 17

Endotoxemia (LPS) can exacerbate ischemic tubular injury and acute renal failure (ARF). The present study tested the following hypothesis: that acute ischemic damage sensitizes the kidney to LPS-mediated TNF-alpha generation, a process that can worsen inflammation and cytotoxicity. CD-1 mice underwent 15 min of unilateral renal ischemia. LPS (10 mg/kg iv), or its vehicle, was injected either 45 min before, or 18 h after, the ischemic event. TNF-alpha responses were gauged 2 h post-LPS injection by measuring plasma/renal cortical TNF-alpha and renal cortical TNF-alpha mRNA. Values were contrasted to those obtained in sham-operated mice or in contralateral, nonischemic kidneys. TNF-alpha generation by isolated mouse proximal tubules (PTs), and by cultured proximal tubule (HK-2) cells, in response to hypoxia-reoxygenation (H/R), oxidant stress, antimycin A (AA), or LPS was also assessed. Ischemia-reperfusion (I/R), by itself, did not raise plasma or renal cortical TNF-alpha or its mRNA. However, this same ischemic insult dramatically sensitized mice to LPS-mediated TNF-alpha increases in both plasma and kidney (approximately 2-fold). During late reperfusion, increased TNF-alpha mRNA levels also resulted. PTs generated TNF-alpha in response to injury. Neither AA nor LPS alone induced an HK-2 cell TNF-alpha response. However, when present together, AA+LPS induced approximately two- to fivefold increases in TNF-alpha/TNF-alpha mRNA. We conclude that modest I/R injury, and in vitro HK-2 cell mitochondrial inhibition (AA), can dramatically sensitize the kidney/PTs to LPS-mediated TNF-alpha generation and increases in TNF-alpha mRNA. That ischemia can "prime" tubules to LPS response(s) could have potentially important implications for sepsis syndrome, concomitant renal ischemia, and for the induction of ARF.
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PMID:Ischemic proximal tubular injury primes mice to endotoxin-induced TNF-alpha generation and systemic release. 1579 91

Acute renal failure (ARF) associated with sepsis has a high rate of mortality. It is not merely a surrogate marker for severity of disease but also an independent predictor of mortality and a separate pathogenic entity, even when nearly physiological doses of fluid and small-molecule clearance are maintained with currently available renal replacement therapies (RRT). The techniques to remove cytokines, including high-volume haemofiltration, haemodialysis using high-cut-off haemofilters, and absorptive techniques, lead to some improvement in outcome but are still insufficient to reverse the complicated biological dysregulation resulting from ARF associated with sepsis. The novel and exciting technique of cell therapy, which is based on the principle of using functional cells to replace a greater range of renal functions, may add significant benefit to current RRT in dealing with this disease process. Because renal tubule cells appear to play critical roles in immunoregulation, renal tubule cell therapy during ARF associated with sepsis should alter the detrimental multiple-organ consequences of sepsis. The development of a bioartificial kidney consisting of a conventional haemofiltration cartridge in series with a renal tubule assist device containing renal proximal tubule cells represents a new therapeutic approach to this clinical disorder. The results to date of large animal studies and recent Phase I/II and Phase II clinical trials show that such a device replaces multiple kidney functions and modifies the sepsis condition to improve survival in ARF.
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PMID:Bioartificial kidney in the treatment of acute renal failure associated with sepsis. 1688 66

The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.
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PMID:Upregulation of renal inducible nitric oxide synthase during human endotoxemia and sepsis is associated with proximal tubule injury. 1769 97

Gentamicin is a mainstay in treating gram-negative sepsis. However, it also may potentiate endotoxin (LPS)-driven plasma TNF-alpha increases. Because gentamicin accumulates in renal tubules, this study addressed whether gentamicin directly alters LPS-driven tubular cell TNF-alpha production. HK-2 proximal tubular cells were incubated for 18 h with gentamicin (10-2,000 microg/ml). Subsequent LPS-mediated TNF-alpha increases (at 3 or 24 h; protein/mRNA) were determined. Gentamicin effects on overall protein synthesis ([(35)S]methionine incorporation), monocyte chemoattractant protein-1 (MCP-1) levels, and LPS-stimulated TNF-alpha generation by isolated mouse proximal tubules also were assessed. Finally, because gentamicin undergoes partial biliary excretion, its potential influence on gut TNF-alpha/MCP-1 mRNAs was probed. Gentamicin caused striking, dose-dependent inhibition of LPS-driven TNF-alpha production (up to 80% in HK-2 cells/isolated tubules). Surprisingly, this occurred despite increased TNF-alpha mRNA accumulation. Comparable changes in MCP-1 were observed. These changes were observed at clinically relevant gentamicin concentrations and despite essentially normal overall protein synthetic rates. Streptomycin also suppressed LPS-driven TNF-alpha increases, suggesting an aminoglycoside drug class effect. Gentamicin doubled basal TNF-alpha mRNA in cecum and in small intestine after LPS. Gentamicin can suppress LPS-driven TNF-alpha production in proximal tubule cells, likely by inhibiting its translation. Overall preservation of protein synthesis and comparable MCP-1 suppression suggest a semiselective blockade within the LPS inflammatory mediator cascade. These results, coupled with increases in gut TNF-alpha/MCP-1 mRNAs, imply that gentamicin may exert protean, countervailing actions on systemic cytokine/chemokine production during gram-negative sepsis.
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PMID:Gentamicin suppresses endotoxin-driven TNF-alpha production in human and mouse proximal tubule cells. 1769 51

Sepsis is the leading cause of morbidity and mortality in intensive care units (ICU). Acute renal failure (ARF) is a common condition, affecting approximately 5% of all hospitalized patients and up to 20% of critically ill patients. The combination of ARF and sepsis is associated with 75% mortality. Hyperglycemia and an increase in plasma lactate concentration are markers of poor prognosis in patients with sepsis; they often precede the onset of multiple organ dysfunction and ARF. Direct online measurement by means of amperometric biosensors would allow the early detection of increasing levels of both glucose and lactate, as well as the possibility to maintain glucose within a well-defined range. Current standards of care in ARF require synthetic membranes that substitute the small solute clearance function of the renal glomerulus, but they do not replace the transport, metabolic and endocrine functions of the renal proximal tubule cells. The application of cell therapy to the successful process of hemofiltration may therefore improve the poor prognosis of patients with ARF in the ICU. An extracorporeal bioartificial kidney consisting of a conventional hemofilter connected to a renal tubule assist device has demonstrated both in animal models of ARF and in phase I/II clinical trials its ability to successfully replace the filtration, transport, metabolic, and endocrine functions of the kidney. To improve the outcome of septic patients with ARF, multidisciplinary interactions and cooperation between basic, clinical and industrial researchers are mandatory; the development of new artificial or biological devices may allow online monitoring of biological parameters and better treatment of septic syndrome and related systemic complications.
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PMID:[Biofilters and biosensors]. 1803 17

The treatment of severe acute kidney injury (AKI) with dialysis or hemofiltration remains suboptimal with high levels of morbidity and mortality. Current renal replacement therapies substitute for the small solute clearance function of the kidney but do not replace the lost reclamation, metabolic and endocrine functions of this organ. Cell therapy and tissue engineering offer hope of fuller replacement of kidney function in renal failure patients. A renal tubule assist device (RAD) that includes a conventional hemodialysis filter and a bioreactor containing living renal proximal tubule cells has been successfully engineered. Differentiated activity of these cells and survival advantages have been demonstrated in large-animal models of sepsis and AKI. Data from phase I/II and phase II clinical studies have shown that the addition of renal tubule cell therapy to conventional continuous renal replacement therapy (CRRT) treatment resulted in a significant clinical impact on survival, and that RAD treatment demonstrated an acceptable safety profile. Another substantive advance for the treatment of AKI will be the development of nanofabrication technology to further improve the clearance function of the kidney to replicate glomerular permselectivity while retaining high rates of hydraulic permeability. New developments in this translational research area will improve the unmet medical needs of patients with renal failure.
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PMID:The bioartificial kidney and bioengineered membranes in acute kidney injury. 1880 74


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