Ghrelin protects mice against endotoxemia-induced acute kidney injury

Acute kidney injury (AKI) in septic patients drastically increases the mortality to 50–80%. Sepsis is characterized by hemodynamic perturbations as well as overwhelming induction of proinflammatory cytokines. Since ghrelin has been shown to have anti-inflammatory properties, we hypothesized that ghrelin may afford renal protection during endotoxemia-induced AKI. Studies were conducted in a normotensive endotoxemia-induced AKI model in mice by intraperitoneal injection of 3.5 mg/kg LPS. Serum ghrelin levels were increased during endotoxemia accompanied by increased ghrelin receptor (GHSR-1a) protein expression in the kidney. Ghrelin administration (1.0 mg/kg sc 6 h and 30 min before and 14 h after LPS) significantly decreased serum cytokine levels (TNF-α, IL-1β, and IL-6) and serum endothelin-1 levels which had been induced by LPS. The elevated serum nitric oxide (NO) levels and renal inducible NO synthase expression were also decreased by ghrelin. Renal TNF-α levels were also increased significantly in response to LPS and ghrelin significantly attenuated this increase. When administrated before LPS, ghrelin protected against the fall in glomerular filtration rate at 16 h (172.9 ± 14.7 vs. 90.6 ± 15.2 μl/min, P < 0.001) and 24 h (147.2 ± 20.3 vs. 59.4 ± 20.7 μl/min, P < 0.05) as well as renal blood flow at 16 h (1.65 ± 0.07 vs. 1.47 ± 0.04 ml/min, P < 0.01) and 24 h (1.56 ± 0.08 vs. 1.22 ± 0.03 ml/min, P < 0.05) after LPS administration without affecting mean arterial pressure. Ghrelin remained renal protective even when it was given after LPS. In summary, ghrelin offered significant protection against endotoxemia-induced AKI. The renal protective effect of ghrelin was associated with an inhibition of the proinflammatory cytokines. Of particular importance was the suppression of TNF-α both in the circulation and kidney tissues. Thus, ghrelin may be a promising peptide in managing endotoxemia-induced AKI.

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Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

AJP Renal Physiology ◽

10.1152/ajprenal.00107.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. F907-F916 ◽

Cited By ~ 49

Author(s):

Ana Andrés-Hernando ◽

Christopher Altmann ◽

Nilesh Ahuja ◽

Miguel A. Lanaspa ◽

Raphael Nemenoff ◽

...

Keyword(s):

Acute Kidney Injury ◽

Lung Injury ◽

Proinflammatory Cytokines ◽

Kidney Injury ◽

Myeloperoxidase Activity ◽

Proinflammatory Response ◽

Sham Surgery ◽

Tnf Α ◽

Anti Inflammatory ◽

Anti Inflammatory Cytokine

Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury.

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Clearance of inflammatory cytokines in patients with septic acute kidney injury during renal replacement therapy using the EMiC2 filter (Clic-AKI study)

Critical Care ◽

10.1186/s13054-021-03476-x ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Nuttha Lumlertgul ◽

Anna Hall ◽

Luigi Camporota ◽

Siobhan Crichton ◽

Marlies Ostermann

Keyword(s):

Acute Kidney Injury ◽

Growth Factor ◽

Replacement Therapy ◽

Kidney Injury ◽

Final Analysis ◽

Adsorptive Capacity ◽

Clearance Rates ◽

Plasma Cytokine ◽

Tnf Α ◽

Ifn Γ

Abstract Background The EMiC2 membrane is a medium cut-off haemofilter (45 kiloDalton). Little is known regarding its efficacy in eliminating medium-sized cytokines in sepsis. This study aimed to explore the effects of continuous veno-venous haemodialysis (CVVHD) using the EMiC2 filter on cytokine clearance. Methods This was a prospective observational study conducted in critically ill patients with sepsis and acute kidney injury requiring kidney replacement therapy. We measured concentrations of 12 cytokines [Interleukin (IL) IL-1β, IL-1α, IL-2, IL-4, IL-6, IL-8, IL-10, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, vascular endothelial growth factor, monocyte chemoattractant protein (MCP)-1, epidermal growth factor (EGF)] in plasma at baseline (T0) and pre- and post-dialyzer at 1, 6, 24, and 48 h after CVVHD initiation and in the effluent fluid at corresponding time points. Outcomes were the effluent and adsorptive clearance rates, mass balances, and changes in serial serum concentrations. Results Twelve patients were included in the final analysis. All cytokines except EGF concentrations declined over 48 h (p < 0.001). The effluent clearance rates were variable and ranged from negligible values for IL-2, IFN-γ, IL-1α, IL-1β, and EGF, to 19.0 ml/min for TNF-α. Negative or minimal adsorption was observed. The effluent and adsorptive clearance rates remained steady over time. The percentage of cytokine removal was low for most cytokines throughout the 48-h period. Conclusion EMiC2-CVVHD achieved modest removal of most cytokines and demonstrated small to no adsorptive capacity despite a decline in plasma cytokine concentrations. This suggests that changes in plasma cytokine concentrations may not be solely influenced by extracorporeal removal. Trial registration: NCT03231748, registered on 27th July 2017.

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α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

AJP Renal Physiology ◽

10.1152/ajprenal.00143.2012 ◽

2012 ◽

Vol 303 (10) ◽

pp. F1443-F1453 ◽

Cited By ~ 46

Author(s):

Chung-Hsi Hsing ◽

Chiou-Feng Lin ◽

Edmund So ◽

Ding-Ping Sun ◽

Tai-Chi Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Histone Deacetylases ◽

Trichostatin A ◽

Histone H3 ◽

Cecal Ligation ◽

Kidney Injury ◽

Protective Effects ◽

Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

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MiR-22-3p suppresses sepsis-induced acute kidney injury by targeting PTEN

Bioscience Reports ◽

10.1042/bsr20200527 ◽

2020 ◽

Vol 40 (6) ◽

Author(s):

Xudong Wang ◽

Yali Wang ◽

Mingjian Kong ◽

Jianping Yang

Keyword(s):

Acute Kidney Injury ◽

Inflammatory Response ◽

Periodic Acid ◽

Kidney Injury ◽

Luciferase Reporter ◽

Tunel Staining ◽

Tnf Α

Abstract Background: Septic acute kidney injury is considered as a severe and frequent complication that occurs during sepsis. The present study was performed to understand the role of miR-22-3p and its underlying mechanism in sepsis-induced acute kidney injury. Methods: Rats were injected with adenovirus carrying miR-22-3p or miR-NC in the caudal vein before cecal ligation. Meanwhile, HK-2 cells were transfected with the above adenovirus following LPS stimulation. We measured the markers of renal injury (blood urea nitrogen (BUN), serum creatinine (SCR)). Histological changes in kidney tissues were examined by hematoxylin and eosin (H&E), Masson staining, periodic acid Schiff staining and TUNEL staining. The levels of IL-1β, IL-6, TNF-α and NO were determined by ELISA assay. Using TargetScan prediction and luciferase reporter assay, we predicted and validated the association between PTEN and miR-22-3p. Results: Our data showed that miR-22-3p was significantly down-regulated in a rat model of sepsis-induced acute kidney injury, in vivo and LPS-induced sepsis model in HK-2 cells, in vitro. Overexpression of miR-22-3p remarkably suppressed the inflammatory response and apoptosis via down-regulating HMGB1, p-p65, TLR4 and pro-inflammatory factors (IL-1β, IL-6, TNF-α and NO), both in vivo and in vitro. Moreover, PTEN was identified as a target of miR-22-3p. Furthermore, PTEN knockdown augmented, while overexpression reversed the suppressive role of miR-22-3p in LPS-induced inflammatory response. Conclusions: Our results showed that miR-22-3p induced protective role in sepsis-induced acute kidney injury may rely on the repression of PTEN.

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Abstract 655: Ischemia-induced Epoxyeicosatrienoic Acid Release Protects Female Rats From Acute Kidney Injury

Hypertension ◽

10.1161/hyp.60.suppl_1.a655 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Duska Dragun ◽

Uwe Hoff ◽

Maximilian Blum ◽

Gordana Bubalo ◽

Mandy Fechner ◽

...

Keyword(s):

Acute Kidney Injury ◽

Creatinine Clearance ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Female Rats ◽

Epoxyeicosatrienoic Acid ◽

Renal Protection ◽

Sham Control ◽

Male And Female ◽

Enhanced Production

Females are naturally protected against ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) in various clinical and experimental settings. However, the underlying mechanisms are unknown. We hypothesized that female protection may be conferred by enhanced production of cytochrome P450 (CYP)-dependent epoxyeicosatrienoic acids (EETs) that promote vasodilation as well as antiinflammatory and antiapoptotic pathways in the kidney. To test this hypothesis, we first analyzed the renal CYP-eicosanoid profile by liquid chromatography tandem mass spectrometry in male and female Lewis rats. Ischemia was induced through 45 min of left renal vessel clamping after right nephrectomy (n=6-8 per group). In non-ischemic controls, male and female kidneys stored almost identical amounts of EETs as well as 20-hydroxyeicosatetraenoic acid (20-HETE), both predominantly esterified into phospholipids, under basal non-ischemic conditions. 45 min of ischemia induced a massive release of EETs from membrane stores in females but not males. The free renal EET-levels reached 70.2±20.1 in females compared to only 4.6±1.3 ng/g in males. After ischemia, the ratio of free EETs to free 20-HETE was about 1:1 in females and 1:3 in males. Next, we proved the functional importance of EETs in renal protection by pretreating males with a synthetic EET-agonist (12-HUDE) and females with a selective EET-antagonist (14,15-EEZE-mSI). As analyzed two days after reperfusion, the EET-agonist protected males against loss of creatinine clearance (1.03±0.18 vs. 0.26±0.02 ml/min, p<0.01 vs. vehicle, compared to 1.28±0.06 ml/min in sham control). Females were rendered susceptible to I/R-injury by the EET-antagonist (creatinine clearance: 0.25±0.05 vs. 0.67±0.04; p<0.01 vs. vehicle, compared to 0.81±0.04 ml/min in sham control). Changes in inflammatory cell infiltration and tubular apoptosis paralleled these effects on renal function. Our results indicate that female rats are protected against renal I/R-injury by enhanced ischemia-induced EET-release and demonstrate that renal protection can be transferred to males using synthetic EET-agonists.

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Genetic association of IL-6, TNF-α and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer

Gene ◽

10.1016/j.gene.2015.03.063 ◽

2015 ◽

Vol 565 (1) ◽

pp. 62-67 ◽

Cited By ~ 24

Author(s):

Umapathy Dhamodharan ◽

Vijay Viswanathan ◽

Ezhilarasi Krishnamoorthy ◽

Rama Rajaram ◽

Vivekanandhan Aravindhan

Keyword(s):

Genetic Association ◽

Diabetic Foot ◽

Foot Ulcer ◽

Diabetic Foot Ulcer ◽

Serum Cytokine ◽

Tnf Α ◽

Cytokine Levels

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Acute Kidney Injury and Atypical Features during Pediatric Poststreptococcal Glomerulonephritis

International Journal of Nephrology ◽

10.1155/2016/5163065 ◽

2016 ◽

Vol 2016 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Rose M. Ayoob ◽

Andrew L. Schwaderer

Keyword(s):

Acute Kidney Injury ◽

Care Center ◽

Tertiary Care ◽

Elevated Serum ◽

Rapidly Progressive Glomerulonephritis ◽

Kidney Injury ◽

Small Subset ◽

Acute Glomerulonephritis ◽

Poststreptococcal Glomerulonephritis ◽

Presenting Symptoms

The most common acute glomerulonephritis in children is poststreptococcal glomerulonephritis (PSGN) usually occurring between 3 and 12 years old. Hypertension and gross hematuria are common presenting symptoms. Most PSGN patients do not experience complications, but rapidly progressive glomerulonephritis and hypertensive encephalopathy have been reported. This paper reports 17 patients seen in 1 year for PSGN including 4 with atypical PSGN, at a pediatric tertiary care center. Seventeen children (11 males), mean age of 8 years, were analyzed. Ninety-four percent had elevated serum BUN levels and decreased GFR. Four of the hospitalized patients had complex presentations that included AKI along with positive ANA or ANCAs. Three patients required renal replacement therapy and two were thrombocytopenic. PSGN usually does not occur as a severe nephritis. Over the 12-month study period, 17 cases associated with low serum albumin in 53%, acute kidney injury in 94%, and thrombocytopenia in 18% were treated. The presentation of PSGN may be severe and in a small subset have associations similar to SLE nephritis findings including AKI, positive ANA, and hematological anomalies.

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Role of cystatin C as a biomarker of acute kidney injury and as an independent long-term predictor of cardiovascular events, mortality and functional outcome

Italian Journal of Medicine ◽

10.4081/itjm.2012.195 ◽

2012 ◽

Author(s):

Carolina Marrani ◽

Teuta Zenjelaj ◽

Daniela Bartoli ◽

Francesco Corradi ◽

Rinaldo Innocenti

Keyword(s):

Acute Kidney Injury ◽

Cystatin C ◽

Cardiovascular Events ◽

Cox Regression ◽

Elevated Serum ◽

Kidney Injury ◽

Serum Cystatin C ◽

Serum Cystatin ◽

Long Term Mortality

Introduction Serum cystatin C measurements as an early biomarker of acute kidney injury (AKI) is gaining acceptance as studies confirm and define its usefulness. The aim of this study is to determine whether increase in serum cystatin C has an impact on long-term mortality, independently from the presence of the kidney injury itself.Materials and methods A retrospective study (20-month follow-up) was conducted in 173 not selected hospitalized patients. According to serum cystatin C concentrations, patients were stratified in risk classes by quartiles (≥0.55 and <1 mg/L; ≥1 and <1.17 mg/L; ≥1.17 and 1.57 mg/L; ≥1.57 and ≤5.29 mg/L). We compared the association of cystatin C levels with the risk for long-term mortality, after adjustment for age, sex, race and heart failure risk factors.Results A relationship with higher serum levels of cystatin C and mortality was found in patients with and without AKI, being stronger in patients without AKI. After multivariate adjustment, the highest quartile of cystatin C (>1.5 mg/L) was associated with a lower risk for long-term mortality. The statistical analysis (Cox regression) of the independent variables as far as mortality is concerned confirmed the significance of our result (RR 3.60; IC 1.73–7.48; p = 0.001).Conclusions In summary, elevated serum cystatin C level (>1.5 mg/L) was strongly and independently associated with negative clinical outcomes such as mortality and cardiovascular events, independently from the kidney injury itself. The dosage of cystatin C might play an important role in clinical practice for the assessment of cardiovascular risk stratification.

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Acute Kidney Injury in Children with Severe Malaria Is Common and Associated with Adverse Hospital Outcomes

Journal of Tropical Pediatrics ◽

10.1093/tropej/fmz057 ◽

2019 ◽

Vol 66 (2) ◽

pp. 218-225

Author(s):

Eunice O Oshomah-Bello ◽

Christopher I Esezobor ◽

Adaobi U Solarin ◽

Fidelis O Njokanma

Keyword(s):

Acute Kidney Injury ◽

Serum Creatinine ◽

Severe Malaria ◽

Complete Blood Count ◽

Univariate Analysis ◽

Elevated Serum ◽

Kidney Injury ◽

Hospital Outcomes ◽

Elevated Serum Creatinine ◽

Sub Saharan

Abstract Background The prevalence of acute kidney injury (AKI) in children with severe malaria in sub-Saharan African may have been underestimated. The study aimed to determine the prevalence of AKI in children with severe malaria and its association with adverse hospital outcomes. Methods At presentation, we measured complete blood count, serum bilirubin, and serum electrolytes, urea and creatinine in children with severe malaria. At 24 h after hospitalization, we repeated serum creatinine measurement. Urine passed in the first 24 h of hospitalization was also measured. We defined AKI and its severity using the Kidney Disease: Improving Global Outcome AKI guidelines. Results The study involved 244 children (53.3% males) with a median age of 3.5 (1.9–7.0) years. One hundred and forty-four (59%) children had AKI, and it reached maximum Stages 1, 2 and 3 in 56 (23%), 45 (18.4%) and 43 (17.6%) children, respectively. The majority (86.1%) with AKI had only elevated serum creatinine. Mortality increased with increasing severity of AKI on univariate analysis but weakened on multiple logistic regression. Mortality was also higher in those with both oliguria and elevated serum creatinine than in those with elevated serum creatinine only (50% vs. 4.8%, p < 0.001). Furthermore, children with AKI spent three days more in hospital than those without AKI (p < 0.001). Conclusions Acute kidney injury complicates severe malaria in 6 out of every 10 children and is commonly identified using elevated serum creatinine. It is also associated with adverse hospital outcome.

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The Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms (rs3063368, rs755622) Predict Acute Kidney Injury and Death after Cardiac Surgery

Journal of Clinical Medicine ◽

10.3390/jcm9092936 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2936

Author(s):

Luisa Averdunk ◽

Jürgen Bernhagen ◽

Karl Fehnle ◽

Harald Surowy ◽

Hermann-Josef Lüdecke ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cardiac Surgery ◽

Migration Inhibitory Factor ◽

Macrophage Migration Inhibitory Factor ◽

Elevated Serum ◽

Kidney Injury ◽

Inhibitory Factor ◽

Macrophage Migration ◽

Promoter Polymorphisms ◽

Risk Of Death

Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT5–7 (rs5844572/rs3063368,“-794”) and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT7) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40–2.88), p = 0.0001). Carriers of CATT7 were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99–33.14), p = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20–2.43), p = 0.003). Multivariate analyses identified CATT7 predictive for AKI (OR 2.13 (1.46–3.09), p < 0.001) and death (OR 5.58 (1.29–24.04), p = 0.021). CATT7 was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT7 allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.

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