Effects of HV-CRRT on PCT, TNF-α, IL-4, IL-6, IL-8 and IL-10 in patients with pancreatitis complicated by acute renal failure

Meprin metalloproteases, composed of α and/or β subunits, consist of membrane-bound and secreted forms that are abundantly expressed in proximal tubules of the kidney as well as secreted into the urinary tract. Previous studies indicated that meprin metalloproteases play a role in pathological conditions such as ischemic acute renal failure and urinary tract infection. The aim of this work was to examine the role of meprins in endotoxemic acute renal failure using meprin α knockout (αKO), meprin β knockout (βKO), and wild-type (WT) mice. Differences among the responses of the genotypes were observed as early as 1 h after challenge with 2.5 mg/kg ip Escherichia coli LPS, establishing roles for meprins in the endotoxemic response. Meprin αKO mice displayed lower blood urea nitrogen levels and decreased nitric oxide levels, indicative of a decreased systemic response to LPS compared with WT and meprin βKO mice. Serum cytokine profiles showed lower levels of IL-1β and TNF–α in the meprin αKO mice within 3 h after LPS challenge and confirmed a role for meprins in the early phases of the host response. Meprin αKO mice were also hyporesponsive to LPS administered to the bladder, exhibiting significantly less bladder edema, leukocyte infiltration, and bladder permeability than WT mice. These data indicate that meprin A contributes to the renal and urogenital pathogenesis of endotoxicity.

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Acute renal failure: determinants and characteristics of the injury-induced hyperinflammatory response

AJP Renal Physiology ◽

10.1152/ajprenal.00072.2006 ◽

2006 ◽

Vol 291 (3) ◽

pp. F546-F556 ◽

Cited By ~ 45

Author(s):

Richard A. Zager ◽

Ali C. M. Johnson ◽

Steve Lund ◽

Sherry Hanson

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Lipoteichoic Acid ◽

Heme Oxygenase 1 ◽

Inos Mrna ◽

Chemokine Production ◽

Tnf Α ◽

Tlr2 Ligand ◽

Tlr4 Ligand ◽

Anti Inflammatory

Acute renal failure (ARF) markedly sensitizes mice to endotoxin (LPS), as evidenced by exaggerated renal cytokine/chemokine production. This study sought to further characterize this state by testing the following: 1) does anti-inflammatory heme oxygenase-1 (HO-1) upregulation in selected ARF models prevent this response? 2) Is the ARF hyperresponsive state specifically triggered by LPS? 3) Does excess iNOS activity/protein nitrosylation participate in this phenomenon? and 4) are upregulated Toll receptors involved? Mice with either 1) rhabdomyolysis-induced ARF (massive HO-1 overexpression), 2) cisplatin nephrotoxicity, 3) or HO-1 inhibition (Sn protoporphyrin) were challenged with either LPS (a TLR4 ligand), lipoteichoic acid (LTA; a TLR2 ligand), or vehicle. Two hours later, renal and plasma TNF-α/mRNA, MCP-1/mRNA, renal nitrotyrosine/iNOS mRNA, and plasma cytokines were assessed. Renal TLR4 was gauged by mRNA and Western blot analysis. Both ARF models markedly hyperresponded to both LPS and LTA, culminating in exaggerated TNF-α, MCP-1, and iNOS/nitrotryosine increments. This was despite the fact that HO-1 exerted anti-inflammatory effects. TLR4 levels were either normal (cisplatin), or markedly depressed (∼50%; rhabdomyolysis) in the ARF kidneys, despite the LPS hyperresponsive state. 1) The ARF kidney can hyperrespond to chemically dissimilar Toll ligands; 2) HO-1 does not prevent this response; 3) excess NO/protein nitrosylation can result; and 4) this hyperresponsiveness can be expressed with either normal or reduced renal TLR4 expression. This suggests that diverse signaling pathways may be involved.

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Endotoxin and cisplatin synergistically induce renal dysfunction and cytokine production in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00158.2007 ◽

2007 ◽

Vol 293 (1) ◽

pp. F325-F332 ◽

Cited By ~ 62

Author(s):

Ganesan Ramesh ◽

Binzhi Zhang ◽

Satoshi Uematsu ◽

Shizuo Akira ◽

W. Brian Reeves

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Renal Dysfunction ◽

Blood Urea Nitrogen ◽

Cytokine Production ◽

Moderate Increase ◽

Urea Nitrogen ◽

Increased Risk ◽

Tnf Α ◽

Synergistic Increase

A major toxicity of the cancer chemotherapeutic agent cisplatin is acute renal failure. Sepsis is a common cause of acute renal failure in humans and patients who receive cisplatin are at increased risk for sepsis. Accordingly, this study examined the interactions between cisplatin and endotoxin in vivo with respect to renal function and cytokine production. Mice were treated with either a single dose of cisplatin or two doses of LPS administered 24 h apart, or both agents in combination. Administration of 10 mg/kg cisplatin had no effect on blood urea nitrogen or creatinine levels throughout the course of the study. LPS resulted in a modest rise in blood urea nitrogen at 24 and 48 h, which returned to normal by 72 h. In contrast, mice treated with both cisplatin and LPS developed severe renal failure and an increase in mortality. Urine, but not serum, TNF-α levels showed a synergistic increase by cisplatin and LPS. Urinary IL-6, MCP-1, KC, and GM-CSF also showed a synergistic increase with cisplatin+LPS treatment. The renal dysfunction induced by cisplatin+LPS was completely dependent on TLR4 signaling and partially dependent on TNF-α production. Increased cytokine production was associated with a moderate increase in infiltrating leukocytes which was not different between cisplatin+LPS and LPS alone. These results indicate that cisplatin and LPS act synergistically to produce nephrotoxicity which may involve proinflammatory cytokine production.

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Effect of Caffeic Acid on Ischemia-Reperfusion-Induced Acute Renal Failure in Rats

Pharmacology ◽

10.1159/000497474 ◽

2019 ◽

Vol 103 (5-6) ◽

pp. 315-319 ◽

Cited By ~ 3

Author(s):

Manas Kinra ◽

Devinder Arora ◽

Jayesh Mudgal ◽

K.S.R. Pai ◽

Chamallamudi Mallikarjuna Rao ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Caffeic Acid ◽

Day Treatment ◽

Ischemia Reperfusion ◽

Necrosis Factor Alpha ◽

Stress Markers ◽

Tnf Α ◽

Antioxidant Defense Enzyme ◽

Factor Alpha

Background: Cyclooxygenase (COX)-lipooxygenase (LOX) pathway plays a key role in the pathogenesis of renal ischemia/reperfusion (IR). Objective: This study was aimed to evaluate the role of dietary phenol caffeic acid (CA), alone and in combination with selective COX-2 inhibitor celecoxib (CEL) in IR-induced acute renal failure (ARF) in rats. Materials and Methods: Renal IR was induced by bilateral occlusion of renal pedicels for 90 min followed by reperfusion for 24 h. Rats were randomized into 4 groups: Sham, IR, CA + IR, and CA + CEL + IR, with 7 day treatment before IR. Serum creatinine (SCr), blood urea nitrogen (BUN), antioxidant enzymes, tumor necrosis factor alpha (TNF-α), and histopathological changes were evaluated in the kidney after IR. Results: Renal IR caused significant derangement in renal function and histology. In the IR group, an increase in lipid peroxidation and decreased antioxidant defense enzyme activity were observed. Pretreatment with CA and CA + CEL showed a significant decrease in the BUN, SCr, TNF-α, oxidative stress markers and corrected the histological changes in the kidney. Conclusion: This study demonstrated the renoprotective potential of CA and combination of CA + CEL in IR-induced ARF in rats. The plausible mechanisms for the efficacy of CA could be attributed to its ability to modulate the COX-LOX system in renal IR.

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P1110IN VITRO CYTOKINE REMOVAL - COMPARISM OF CONVENTIONAL HDF AND HDX (MIDDLE-CUT-OFF-DIALYZER, BAXTER THERANOVA)

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1110 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Sebastian Koball ◽

Andreas Koertge ◽

Benjamin Heskamp ◽

Silvius Frimmel ◽

Michael Hinz ◽

...

Keyword(s):

Renal Failure ◽

Blood Flow ◽

Acute Renal Failure ◽

Real World ◽

High Volume ◽

Chronic Dialysis ◽

Total Serum ◽

High Flux ◽

Dialysis Patients ◽

Tnf Α

Abstract Background and Aims The removal of inflammatory mediators and cytokines is of great importance in the treatment of patients with acute or chronic renal failure. In patients with acute renal failure and sepsis, an attempt is made to achieve removal through the use of high-volume treatments or adsorbers in order to achieve better circulatory stability. In chronic dialysis patients, this has so far not been sufficiently addressed, but is important for mortality and cardiovascular events (MIA syndrome). Some studies show a superiority of HDF over conventional HD. By using new MCO filters in HD mode such as the Baxter Theranova (HDx), an improvement of cytokine status seems to be possible in both areas (chronic and acute). The effectiveness of MCO filters (HDx) compared to high flux hemodiafiltration in the removal of interleukins (interleukin 6, interleukin 10 and TNF (tumor necrosis factor) alpha will be assessed. Method The efficacy of HDx was compared with that of conventional high-flux dialysis filters (Fresenius FX80, HDF) in HDF mode. Based on real world conditions the ultrafiltration/substitution rate was set to 50 ml/min. (blood flow 200 ml/min., dialysate flow 500 ml/min.) No effective ultrafiltration was used. The measurements were performed in vitro in a 3l pool of fresh frozen plasma (citrate anticoagulated, with additional heparin during dialysis treatment). IL6 (24.5 kDa) IL10 (18.6 kDa, dimer)) and TNFalpha (17.4 kDa, trimer) were added to the plasma pool in concentrations of 1.5 μg/l each. This results in very high cytokine levels, as for example in severe sepsis. Samples were taken before and after the dialyzer for 180 minutes (after 5, 15, 30, 60, 120 and 180 minutes).For HDF the measured cytokine concentration was corrected for ultrafiltration rates. In addition to cytokines, albumin and total protein concentration were measured (ELISA Kit LEGEND MAX Human IL-6 / IL-10 / TNF-α; Biolegend and Cobas Mira Plus; Roche Kit LT-AB 0103 and LT-TP 0253). Every test was repeat 5 times. Results Theranova HDx showed higher removal rates of all tested cytokines over a period of 180 minutes. A comparison of the concentrations at the beginning and end of the measurements showed: IL-6 reduction - HDx about 77% / HDF about 63%. IL-10 reduction - HDx about 53% and HDF about 22%. TNF-α Reduction - HDx about 26%; HDF about 18% The concentration of albumin and total serum protein was not significant different during the treatments in both groups. Conclusion Hemodialysis therapy with Theranova HDx appears to be a superior or equal therapy option for the removal of cytokines. This opens up new treatment options for both acute renal failure and chronic dialysis patients, especially if citrate anticoagulation is necessary. The ultrafiltration rate in HDF was lower than recommended for high volume diafiltration,but as high as in our real world experience. Therefore the effect of HDF could be underestimated. Clinical studies with clinically relevant blood flow and ultrafiltration rates are still necessary.

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TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure

AJP Renal Physiology ◽

10.1152/ajprenal.00101.2003 ◽

2003 ◽

Vol 285 (4) ◽

pp. F610-F618 ◽

Cited By ~ 175

Author(s):

Ganesan Ramesh ◽

W. Brian Reeves

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Mouse Kidney ◽

Mrna Levels ◽

Wild Type ◽

Cisplatin Nephrotoxicity ◽

Tnf Α ◽

Apoptosis And Necrosis ◽

Deficient Mice

Cisplatin produces acute renal failure in humans and mice. Previous studies have shown that cisplatin upregulates the expression of TNF-α in mouse kidney and that inhibition of either the release or action of TNF-α protects the kidney from cisplatin-induced nephrotoxicity. In this study, we examined the effect of cisplatin on the expression of TNF receptors TNFR1 and TNFR2 in the kidney and the role of each receptor in mediating cisplatin nephrotoxicity. Injection of cisplatin into C57BL/6 mice led to an upregulation of TNFR1 and TNFR2 mRNA levels in the kidney. The upregulation of TNFR2 but not TNFR1 was blunted in TNF-α-deficient mice, indicating ligand-dependent upregulation of TNFR2. To study the roles of each receptor, we administered cisplatin to TNFR1- or TNFR2-deficient mice. TNFR2-deficient mice developed less severe renal dysfunction and showed reduced necrosis and apoptosis and leukocyte infiltration into the kidney compared with either TNFR1-deficient or wild-type mice. Moreover, renal TNF-α expression, ICAM-1 expression, and serum TNF-α levels were lower in TNFR2-deficient mice compared with wild-type or TNFR1-deficient mice treated with cisplatin. These results indicate that TNFR2 participates in cisplatin-induced renal injury in mice and may play an important role in TNF-α-mediated inflammation in the kidney in response to cisplatin.

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Endotoxin and cisplatin synergistically stimulate TNF-α production by renal epithelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00277.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. F812-F819 ◽

Cited By ~ 42

Author(s):

Ganesan Ramesh ◽

Scot R. Kimball ◽

Leonard S. Jefferson ◽

W. Brian Reeves

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Epithelial Cells ◽

P38 Mapk ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Dependent Manner ◽

Renal Epithelial Cells ◽

Cisplatin Nephrotoxicity ◽

Tnf Α

Acute renal failure often occurs in the clinical setting of multiple renal insults. Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of cisplatin nephrotoxicity, ischemia-reperfusion injury, and endotoxin-induced acute renal failure. The current studies examined the interactions between cisplatin and endotoxin with particular emphasis on TNF-α production. Treatment of cultured murine proximal tubule cells (TKPTS cells) with cisplatin resulted in a modest production of TNF-α, while treatment with endotoxin did not result in any TNF-α production. However, the combination of cisplatin and endotoxin resulted in large amounts of TNF-α synthesis and secretion. The stimulation of TNF-α production was dependent on cisplatin-induced activation of p38 MAPK and was associated with phosphorylation of the translation initiation factor eIF4E and its upstream kinase Mnk1. Inhibition of p38 MAPK and, to a lesser extent, ERK, reduced cisplatin+endotoxin-stimulated TNF-α production and phosphorylation of Mnk1 and eIF4E. Synergy between cisplatin and endotoxin was also observed in certain tumor cell lines, but not in macrophages. In macrophages, in contrast to TKPTS cells, endotoxin alone activated p38 MAPK and stimulated TNF-α production with no added impact by cisplatin. The combination of cisplatin and endotoxin did not result in synergistic production of other cytokines, e.g., MCP-1 and MIP2, by TKPTS cells. In summary, these studies indicate that cisplatin sensitizes renal epithelial cells to endotoxin and dramatically increases the translation of TNF-α mRNA in a p38 MAPK-dependent manner. These interactions between cisplatin and endotoxin may be relevant to the pathogenesis of cisplatin nephrotoxicity in humans.

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Pentoxifylline protects against endotoxin-induced acute renal failure in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00517.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. F1090-F1095 ◽

Cited By ~ 39

Author(s):

Wei Wang ◽

Einath Zolty ◽

Sandor Falk ◽

Veena Basava ◽

Leonid Reznikov ◽

...

Keyword(s):

Renal Failure ◽

Acute Renal Failure ◽

Wild Type ◽

Renal Protection ◽

Cell Deformability ◽

Tnf Α ◽

Pathogenetic Factor ◽

Factor Α ◽

Renal Vascular ◽

Necrosis Factor

Acute renal failure (ARF) in septic patients drastically increases the mortality to 50–80%. Sepsis induces several proinflammatory cytokines including tumor necrosis factor-α (TNF-α), a major pathogenetic factor in septic ARF. Pentoxifylline has several functions including downregulation of TNF-α and endothelia-dependent vascular relaxation. We hypothesized that pentoxifylline may afford renal protection during endotoxemia either by downregulating TNF-α and/or by improving endothelial function. In wild-type mice, pentoxifylline protected against the fall in glomerular filtration rate (GFR; 105.2 ± 6.6 vs. 50.2 ± 6.6 μl/min, P < 0.01) at 16 h of LPS administration (2.5 mg/kg ip). This renal protective effect of pentoxifylline was associated with an inhibition of the rise in serum TNF-α (1.00 ± 0.55 vs. 7.02 ± 2.40 pg/ml, P < 0.05) and serum IL-1β (31.3 ± 3.6 vs. 53.3 ± 5.9 pg/ml, P < 0.01) induced by LPS. Pentoxifylline also reversed the LPS-related increase in renal iNOS and ICAM-1 and rise in serum nitric oxide (NO). Enhanced red blood cell deformability by pentoxifylline may have increased shear rate and upregulated eNOS. Studies were therefore performed in eNOS knockout mice. The renal protection against endotoxemia with pentoxifylline was again observed as assessed by GFR (119.8 ± 18.0 vs. 44.5 ± 16.2 μl/min, P < 0.05) and renal blood flow (0.86 ± 0.08 vs. 0.59 ± 0.05 ml/min, P < 0.05). Renal vascular resistance significantly decreased with the pentoxifylline (91.0 ± 5.8 vs. 178.0 ± 7.6 mmHg·ml−1·min−1, P < 0.01). Thus pentoxifylline, an FDA-approved drug, protects against endotoxemia-related ARF and involves a decrease in serum TNF-α, IL-1β, and NO as well as a decrease in renal iNOS and ICAM-1.

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