Inflammation In Acute Kidney Injury Research Articles

Numb ameliorates necrosis and inflammation in acute kidney injury induced by cisplatin

Cisplatin induces acute renal failure in humans and mice.Tubular apoptosis, necrosis and inflammation are the primary pathogenesis of cisplatin-induced acute kidney injury(AKI). We previously reported that the depletion of Numb from proximal tubules exacerbates tubular cells apoptosis in cisplatin-induced AKI, however, the role of Numb in tubular necrosis and renal inflammation in cisplatin-induced AKI remains unclear. A mouse model of AKI was produced by cisplatin intraperitoneally injection in mice from proximal tubule-specific depletion of Numb (PT-Nb-KO) and their wild-type littermates (PT-Nb-WT) respectively. Renal Numb expression was determined by Western blotting. Renal morphological damage was examined by hematoxylin and eosin staining (H&E staining). Tubular necrosis was evaluated by histological study and the protein level of renal Mixed lineage kinase domain-like protein (MLKL) which is a molecular marker of necrosis. Leukocyte infiltration and pro-inflammatory cytokines was determined by immunostaining and quantitative real-time PCR (qRT-PCR) respectively.The protein level of Numb was dramatically decreased in kidneys of PT-Nb-KO mice compared with PT-Nb-WT mice. After cisplatin injection, a significant increase of tubular injury score and the protein level of renal MLKL were detected in PT-Nb-KO mice compared with those in PT-Nb-WT. In addition, the number of F4/80-positve and CD3-positive cells, markers for macrophages and neutraphils respectively, showed significantly increased in kidneys from PT-Nb-KO mice compared with those in PT-Nb-WT mice. Consistently, the gene expression of pro-inflammatory cytokines including TNF-α and MCP-1 in the kidneys was higher in PT-Nb-KO mice than those in PT-Nb-WT mice. Numb play additional protective role in cisplatin-induced AKI through ameliorating tubular necrosis and renal inflammation besides attenuating cisplatin-induced tubular apoptosis.

GASDERMIN-D MUTATION IS PROTECTIVE AGAINST RENAL ISCHEMIA REPERFUSION INJURY

Introduction: Ischemia reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and delayed graft function following kidney transplantation. The desire to limit IRI and graft injury has driven further exploration of the underlying pathophysiology. We hypothesize that pyroptosis, a pro-inflammatory form of cell death, has an important role in IRI and AKI. This pathway converges to the downstream cleavage and of the Gasdermin-D protein, resulting in the release of the N-terminus and pore formation in the cell membrane and cell death. We examine the effects of Gasdermin-D mutation on inflammation in acute kidney injury. Materials and Methods: Male C57BL/6 mice were exposed to ethyl-N-nitrosourea mutagenesis, leading to a loss-of-function, single nucleotide polymorphism (isoleucine to asparagine mutation, I105N) in the Gasdermin-D gene. Age- and gender-matched littermate control wild-type, heterozygous and homozygous Gasdermin-D mice were subjected to bilateral renal IRI (36 degrees Celcius, 22 min) and sacrificed 24-hours post-reperfusion for assessment of renal function, histology and biomolecular phenotyping. Similar experiments were performed with chimeric mice to delineate if a mutation in the parenchyma (kidney) or hematopoietic (particularly immune) cells drive the key effects of pyroptosis in IRI. Chimers were created with by whole body irradiation of the recipient mouse, followed by infusion of syngeneic donor bone marrow. The impact of bilateral renal IRI was assessed 8-weeks post-engraftment. Results and Discussion: Homozygote (HOM) and heterozygote Gasdermin-DI105N mice were protected from renal IRI in a gene-related, dose-dependent manner when compared to wild-type (WT), with lower mean serum creatinine (15.7, 48.1 and 85.5µmol/L respectively, p<0.001), less histological tubular injury and cell death (1.8, 3.6 and 5.1 TUNEL+ve cells/hpf, p<0.01). Mutant mice also had reduced expression of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, RANTES). This data supports the hypothesis that Gasdermin-D and the pyroptosis pathway has significant impact on the severity of renal injury and has an important role in renal IRI. Chimeric models indicated that susceptibility to IRI may be driven by the parenchymal (renal tubular) cells when matched for age, gender and recipient mutation status. There was no significant difference in serum creatinine in HOM Gasdermin-D mice receiving bone marrow from either HOM or WT donor (36.5 vs 56 µmol/L respectively, p=0.72), nor was there difference in the WT mice receiving bone marrow from HOM or WT donors (114.5 vs 128.5 µmol/L respectively, p=0.96). Conclusion: Mice with impaired pyroptosis, from loss-of-function mutation in the Gasdermin-D (I105N), were protected from renal IRI. This clearly demonstrates the importance of the pyroptosis in acute kidney injury and manipulation of this pathway is an attractive target to mitigate inflammation and cellular death following injury.

C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury.

Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.

MO066GASDERMIND MUTATION IS PROTECTIVE AGAINST RENAL ISCHEMIA REPERFUSION INJURY

Abstract Background and Aims Ischemia reperfusion injury (IRI) is an important contributor to acute kidney injury (AKI) and manifests as delayed graft function following kidney transplantation. Limiting the damage of IRI has implications on graft outcomes and has driven further exploration of the underlying pathophysiology. We hypothesize that pyroptosis, a pro-inflammatory form of cell death, has an important role in IRI and AKI. The pyroptosis pathway converges to the cleavage and release of N-terminal of the Gasdermin-D protein, leading to pore formation in the cell membrane and cell death. We examined the effects of Gasdermin-D mutation on inflammation in acute kidney injury. Method Male C57BL/6 mice were exposed to ethyl-N-nitrosourea mutagenesis, leading to a loss-of-function, single nucleotide polymorphism (isoleucine to asparagine mutation, I105N) in the Gasdermin-D gene. Age- and gender-matched littermate control wild-type, heterozygous and homozygous Gasdermin-DI105N mice were subjected to bilateral renal IRI (36°C, 22mins) and sacrificed 24-hours post-reperfusion for analysis of renal function, histology and biomolecular phenotyping. To delineate if the GasderminD mutation in renal parenchymal or hematopoietic cells were key drivers of IRI, we generated chimeric mice with whole body irradiation and infusion of syngeneic donor bone marrow. Following 8 weeks of engraftment, bilateral renal IRI was performed with analysis at 24 h reperfusion. Results Homozygote and heterozygote Gasdermin-DI105N mice were protected from renal IRI in a gene dose-dependent manner when compared to wild-type, with lower mean serum creatinine (15.7, 48.1 and 85.5µmol/L respectively, p&amp;lt;0.001), less histological tubular injury and cell death (1.8, 3.6 and 5.1 TUNEL+ cells/hpf, p&amp;lt;0.01) and significantly decreased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, RANTES). Homozygote GasderminDI105N chimeric mice (reconstituted with wild-type donor bone marrow) were more susceptible to IRI, and serum creatinine was similar to that of wild-type chimeric control mice, indicating that hematopoietic cells rather than parenchymal cells, are likely predominant drivers of injury. Similarly, adoptive transfer of CpG-activated CD11c+ dendritic cells into homozygous Gasdermin-DI105N mice augmented renal injury compared to GpC-treated cells. Conclusion GasderminDI105N mice were protected from IRI and demonstrates the importance of the pyroptosis pathway on acute kidney injury. Manipulation of GasderminD is potentially an attractive target to mitigate inflammation and cellular death following injury.

P0530A NOVEL LNCRNA(LRAN9884) PROMOTES AKI VIA MAINTAINING MINCLE-DEPENDENT M1 MACROPHAGE PHENOTYPE

Abstract Background and Aims Macrophages are key inflammatory cells and play a critical role in renal inflammation in acute kidney injury (AKI). M1 inflammatory macrophage and M2 anti-inflammatory macrophage act reverse role. Phenotype of macrophages is highly flexible and can be changed over time. However, the underlying mechanism of M1 and M2 macrophage phenotype switching during AKI is still largely unclear. In our previous study, we identified a novel lncRNA (LRNA9884) might contribute to inflammation according to modifying macrophages. The present study was designed to uncover the pathogenic role and the underlying mechanism of LRNA9884 in cisplatin-induced AKI. Method Expression level and pattern of LRNA9884 were examined in cisplatin-induced AKI mice. The regulatory mechanisms of LRNA9884 was investigated in cultured bone marrow–derived macrophages (BMDMs) in vitro by silencing or overexpressing of LRNA9884. Flow Cytometer, fluorescence in situ hybridization (FISH) and other multiple molecular biological techniques were applied to figure out the role of LRNA9884 under acute kidney injury. Results LRNA9884 was significantly upregulated in the kidney of cisplatin-induced mice and was associated with the progression of the renal inflammation by using RT-PCR and ISH assay. FISH assay with immunofluorescence co-staining detected that LRNA9884 was largely expressed in the nucleus of macrophage in cisplatin-induced mice kidney compared with the sham group at day 1 after AKI injury. LRNA9884 was remarkedly induced by TNF-α (10ng/ml) in BMDMs as time- and dose- dependent. Western blot and RT-PCR showed that silencing of LRNA9884 effectively inhibited upregulated of macrophage-inducible C-type lectin (Mincle) and iNOS induced by TNF-α. More importantly, we identified that LRNA9884 maintained M1 macrophages phenotype by triggering mincle production at transcriptional level as evidenced by ChIP assay. Conclusion LRNA9884 is a mincle-dependent lncRNA that highly-expressed in macrophages under AKI development. Targeting of LRNA9884 effectively blocked the inflammatory response via promoting the transition M1 macrophage to M2 macrophage phenotype. This study will shed new lights on the understanding of pathological role of novel LRNA9884 in AKI.

Cyclophilin A Promotes Inflammation in Acute Kidney Injury but Not in Renal Fibrosis.

Cyclophilin A (CypA) is a highly abundant protein in the cytoplasm of most mammalian cells. Beyond its homeostatic role in protein folding, CypA is a Damage-Associated Molecular Pattern which can promote inflammation during tissue injury. However, the role of CypA in kidney disease is largely unknown. This study investigates the contribution of CypA in two different types of kidney injury: acute tubular necrosis and progressive interstitial fibrosis. CypA (Ppia) gene deficient and wild type (WT) littermate controls underwent bilateral renal ischaemia/reperfusion injury (IRI) and were killed 24 h later or underwent left unilateral ureteric obstruction (UUO) and were killed 7 days later. In the IRI model, CypA−/− mice showed substantial protection against the loss of renal function and from tubular cell damage and death. This was attributed to a significant reduction in neutrophil and macrophage infiltration since CypA−/− tubular cells were not protected from oxidant-induced cell death in vitro. In the UUO model, CypA−/− mice were not protected from leukocyte infiltration or renal interstitial fibrosis. In conclusion, CypA promotes inflammation and acute kidney injury in renal IRI, but does not contribute to inflammation or interstitial fibrosis in a model of progressive kidney fibrosis.

Transcriptome sequencing of circular RNA reveals a novel circular RNA-has_circ_0114427 in the regulation of inflammation in acute kidney injury.

Acute kidney injury (AKI) is a common serious syndrome characterized by rapid decrease of glomerular filtration rate and the progressive increase of serum creatinine. Circular RNAs (circRNAs) are regulatory RNAs that recently became popular among various diseases. However, the expression profile and function of circRNAs in AKI remain largely unknown. The main function of circRNAs is acting as competing endogenous RNAs (ceRNAs) by binding with microRNAs (miRNAs), as indicated by recent research. In the present study, we established cisplatin-induced AKI model in mice and isolated renal tubular tissues to extract circRNAs for next-generation sequencing (NGS) and bioinformatics analysis. We analyzed the composition, distribution and Gene Ontology terms of circRNAs in cisplatin-induced AKI and revealed differentially expressed circRNAs related to AKI. By finding homologous genes between mouse and human, we identified circRNA- circ-0114427 in humans. We further investigated its function in AKI cell model. Circ-0114427 expression was significantly up-regulated in different AKI cell models. Knockdown of circ-0114427 indicated that circ-0114427 bound to miR-494 as a miRNA sponge to regulate ATF3 expression and further affected the expression of downstream cytokine IL-6. Circ-0114427 regulates inflammatory progression in AKI's early stage via circ-0114427/miR-494/ATF3 pathway. Our findings reveal the expression profile of circRNAs in cisplatin-induced AKI and provide a novel insight into the regulatory mechanism of circRNAs, which may become a new molecular target resource for early diagnosis and treatment strategies.

Role of promoting inflammation of Krüppel-like factor 6 in acute kidney injury

Background Krüppel-like factor 6 (KLF6) is a transcription factor that participate in various pathophysiological processes, but its contribution in ischemia acute kidney injury (AKI) is lacking so far. The study aimed to investigate the expression and the role of KLF6 in kidney ischemia–reperfusion (IR) injury. Method Microarray data were collected from GSE58438 and GSE52004. The rat IR model was established to evaluate the mRNA and protein expression of KLF6 and inflammatory cytokines in serum and kidney tissues. SiRNA-KLF6 was transfected with HK-2 cells, and then a cell-based hypoxia-reoxygenation (HR) model was established. Results Bioinformatics showed KLF6 mRNA in kidney tissue is up-regulated in 3 h after IR in rat kidney, which involved in cell activation, leukocyte activation, and response to hydrogen peroxide after IR. The rat IR model results showed that KLF6 expression was peaking at 6 h, and the expression of pro-inflammatory cytokines MCP-1 and TNF-α was increased both in serum and kidney tissues, while anti-inflammatory cytokine IL-10 was decreased after IR. Furthermore, in vitro results showed that KLF6 knock-down reduced the pro-inflammatory cytokines expression. Conclusion These results suggest that (1) KLF6 might be a novel biomarker for early diagnosis of AKI and (2) KLF6 may play a role in promoting inflammation in AKI.

Inflammation as a predictor of acute kidney injury and mediator of higher mortality after acute kidney injury in non-cardiac surgery

This retrospective cohort study examined the roles of inflammation in acute kidney injury (AKI). Serum albumin and C-reactive protein (CRP) were used as markers of inflammation. Adults who underwent non–cardiac surgery from 2007 to 2011 were included. Exclusion criteria were urological surgery, obstetric surgery, missing data, and pre-operative dialysis. Subjects were followed until the end of 2015 or loss to follow-up. Associations between pre–operative albumin or CRP and post-operative AKI or association between AKI and mortality were examined by logistic or Cox regression, respectively. Mediation analyses were performed using albumin and CRP as mediators. Among 4,538 subjects, 272 developed AKI. Pre-operative albumin was independently associated with AKI (odds ratio [95% confidence interval (CI)]: 0.63 [0.48–0.83]). During a median follow-up of 4.5 years, 649 died. AKI was significantly associated with mortality (hazard ratio [HR] [95% CI]: 1.58 [1.22–2.04]). Further adjustment for pre-operative albumin and CRP attenuated the association (HR [95% CI]: 1.28 [0.99–1.67]). The proportions explained by mediating effects of lnCRP and albumin were 29.3% and 39.2% and mediation effects were statistically significant. In conclusion, inflammation is a predictor of AKI and a mediator of mortality after AKI. Interventions targeting inflammation might improve outcomes of AKI.

Urine neutrophil gelatinase‐associated lipocalin to diagnose and characterize acute kidney injury in dogs

BackgroundUrine neutrophil gelatinase‐associated lipocalin (NGAL) is a promising biomarker of acute kidney injury (AKI) in dogs.ObjectivesTo evaluate the utility of urinary NGAL for characterizing AKI according to volume responsiveness, presence of inflammation and sepsis, and prognosis.AnimalsDogs with AKI (n = 76) and healthy controls (n = 10).MethodsProspective study. Clinical and clinicopathologic data including absolute urine NGAL concentration (uNGAL) and NGAL normalized to urine creatinine concentration (uNGALC) were measured upon admission. Dogs were graded according to International Renal Interest Society (IRIS) AKI guidelines and compared based on AKI features: volume‐responsive (VR‐) AKI vs. intrinsic (I‐) AKI based on IRIS criteria; VR‐AKI and I‐AKI based on urine chemistry; inflammatory versus noninflammatory; septic versus nonseptic; and survivors versus nonsurvivors. Nonparametric statistics were calculated, and significance set at P < .05.ResultsUrinary NGAL was significantly higher in dogs with AKI compared to controls, regardless of AKI grade. Urinary NGAL did not differ between dogs with VR‐AKI and I‐AKI based on IRIS criteria, whereas higher uNGALC was recorded in dogs with I‐AKI based on urine chemistry. Urinary NGAL was significantly higher in dogs with inflammatory AKI, whereas no difference with respect to sepsis or outcome was identified.Conclusions and Clinical ImportanceUrinary NGAL is a sensitive marker for AKI in dogs, but its specificity is affected by systemic inflammation. Increased urinary NGAL in both I‐AKI and VR‐AKI also suggests the presence of tubular damage in transient AKI. Combining urine chemistry data with IRIS criteria could facilitate AKI characterization in dogs.

Novel Immunomodulatory Cytokine Regulates Inflammation, Diabetes, and Obesity to Protect From Diabetic Nephropathy.

Obesity-linked (type 2) diabetic nephropathy (T2DN) has become the largest contributor to morbidity and mortality in the modern world. Recent evidences suggest that inflammation may contribute to the pathogenesis of T2DN and T-regulatory cells (Treg) are protective. We developed a novel cytokine (named IL233) bearing IL-2 and IL-33 activities in a single molecule and demonstrated that IL233 promotes Treg and T-helper (Th) 2 immune responses to protect mice from inflammatory acute kidney injury. Here, we investigated whether through a similar enhancement of Treg and inhibition of inflammation, IL233 protects from T2DN in a genetically obese mouse model, when administered either early or late after the onset of diabetes. In the older mice with obesity and microalbuminuria, IL233 treatment reduced hyperglycemia, plasma glycated proteins, and albuminuria. Interestingly, IL233 administered before the onset of microalbuminuria not only strongly inhibited the progression of T2DN and reversed diabetes as indicated by lowering of blood glucose, normalization of glucose tolerance and insulin levels in islets, but surprisingly, also attenuated weight gain and adipogenicity despite comparable food intake. Histological examination of kidneys showed that saline control mice had severe inflammation, glomerular hypertrophy, and mesangial expansion, which were all attenuated in the IL233 treated mice. The protection correlated with greater accumulation of Tregs, group 2 innate lymphoid cells (ILC2), alternately activated macrophages and eosinophils in the adipose tissue, along with a skewing toward T-helper 2 responses. Thus, the novel IL233 cytokine bears therapeutic potential as it protects genetically obese mice from T2DN by regulating multiple contributors to pathogenesis.Short Description: A novel bifunctional cytokine IL233, bearing IL-2 and IL-33 activities reverses inflammation and protects from type-2 diabetic nephropathy through promoting T-regulatory cells and type 2 immune response.

Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/Axl[sbnd]NF[sbnd]κB/Nrf2 axis

Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.

Immune cells and inflammation in AKI to CKD progression.

Acute kidney injury (AKI) is a common clinical state resulting from pathogenic conditions such as ischemic and toxic insults. The pathophysiology of AKI shares common pathogenic denominators including cell death/injury, inflammation, and fibrosis, regardless of the initiating insults. Recent clinical studies have shown that a single episode of AKI can lead to subsequent chronic kidney disease (CKD). Although the involvement of multiple types of cells in the pathophysiology of AKI is becoming increasingly clear, the precise mechanisms for this "AKI to CKD progression" are still unknown, and no drug has been shown to halt this progression. An increasing number of epidemiological studies have also revealed that the presence of aging greatly increases the risk of AKI to CKD progression, and chronic inflammation is increasingly recognized as an important determinant factor for this progression. In this review article, we first describe the current understanding of the pathophysiology of AKI to CKD progression based on multiple types of cells. In particular, we will highlight the recent findings in regard to the mechanisms for chronic inflammation after AKI. Subsequently, we will focus on the mechanisms responsible for the increased risk of AKI to CKD progression in the elderly. Finally, we highlight our recent finding of age-dependent tertiary lymphoid tissue formation and its roles in AKI to CKD progression and speculate on the potential therapeutic opportunities that come from targeting aberrant inflammation after AKI.

Ischemic modified albumin increases in acute kidney injury

Abstract Purpose: Acute kidney injury (AKI) is a severe kidney disease carrying high morbidity and mortality. An ischemic process, at the cellular level, has been detected prior to the full-blown AKI. An elevated ischemic modified albumin (IMA) was also found to be increased fast at several minutes following an ischemic process in the body. In this connection, we have investigated, in advance, the changes of IMA concentrations in patients with possible AKI. Methods: IMA and other biochemical and haematological parameters were measured in sera of thirty nine patients with AKI and of thirty eight healthy controls. AKI is defined by an increase in serum creatinine by ≥ 0.3 mg/dl in 48 hours or an increase by ≥ 1.5-fold from a known or assumed baseline. The results in the two groups were compared. Results: IMA, creatinine, blood urea nitrogen, white blood cell, neutrophil, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and mean platelet volume were found to be higher in patients with AKI than in healthy controls. In contrast, total protein, albumin, lymphocyte, and haemoglobin were lower in patients with AKI than in healthy controls. No significant difference was recorded in platelet counts between the two groups. Conclusion: Our results indicate that increased levels of NLR and PLR play a central role in a systemic inflammation in AKI. Monitoring serum IMA could be a useful tool in the assessment of AKI.

Targeting Nrf2 in Protection Against Renal Disease.

Renal disease is a serious health problem, with increasing incidence and prevalence. Oxidative stress and inflammation play a key role in the pathogenesis and progression of renal disease. Therefore, therapeutic approaches to decrease oxidative stress should be of interest. This review aims to provide a comprehensive and updated overview of the protective mechanisms mediated by Nrf2 (nuclear factor erythroid 2-related factor 2), a description of novel compounds that target Nrf2, its effectiveness to prevent renal disease and the on-going clinical trials for this pathological condition. We undertook a structured search of bibliographic databases for peer-reviewed research in literature about Nrf2 activators and renal disease. The transcription factor Nrf2 is an emerging regulator of cellular resistance to oxidants and inflammation. Nrf2 controls the basal and induced expression of a couple of cytoprotective and antiinflammatory genes that regulate the physiological and pathophysiological outcomes of oxidant exposure. We have analyzed numerous findings showing that Nrf2 induction protects against oxidative stress and modulates inflammation in acute kidney injury and chronic kidney disease progression. However, few clinical trials have been performed in humans. Recent studies suggested that renoprotective effects of Nrf2 activation are observed at low doses, whereas harmful effects appear at higher concentrations. The findings of this review confirm that novel studies are necessary to address whether Nrf2-targeting may be a safe therapeutic approach to decrease renal disease progression in humans.

Association of low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill*

Given the importance of inflammation in acute kidney injury and the relationship between vitamin D and inflammation, we sought to elucidate the effect of vitamin D on acute kidney injury. We hypothesized that deficiency in 25-hydroxyvitamin D prior to hospital admission would be associated with acute kidney injury in the critically ill. Two-center observational study of patients treated in medical and surgical intensive care units. Two hundred nine medical and surgical intensive care beds in two teaching hospitals in Boston, Massachusetts. Two thousand seventy-five patients, aged ≥ 18 yrs, in whom serum 25-hydroxyvitamin D was measured prior to hospitalization between 1998 and 2009. : None. The exposure of interest was preadmission serum 25-hydroxyvitamin D and categorized a priori as deficiency (25-hydroxyvitamin D <15 ng/mL), insufficiency (25-hydroxyvitamin D 15-30 ng/mL), or sufficiency (25-hydroxyvitamin D ≥ 30 ng/mL). The primary outcome was acute kidney injury defined as meeting Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) Injury or Failure criteria. Logistic regression examined the RIFLE criteria outcome. Adjusted odds ratios were estimated by multivariate logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive of acute kidney injury. Patients with 25-hydroxyvitamin D deficiency have an odds ratio for acute kidney injury of 1.73 (95% confidence interval 1.30-2.30; p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of acute kidney injury following multivariable adjustment (adjusted odds ratio 1.50; 95% confidence interval 1.42-2.24; p < .0001). Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for acute kidney injury of 1.49 (95% confidence interval 1.15-1.94; p = .003) and an adjusted odds ratio of 1.23 (95% confidence interval 1.12-1.72; p = .003) relative to patients with 25-hydroxyvitamin D sufficiency. In addition, preadmission 25-hydroxyvitamin D deficiency is predictive of mortality. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for 30-day mortality of 1.60 (95% confidence interval 1.18-2.17; p = .003) and an adjusted odds ratio of 1.61 (95% confidence interval 1.06-1.57; p = .004) relative to patients with 25-hydroxyvitamin D sufficiency. Deficiency of 25-hydroxyvitamin D prior to hospital admission is a significant predictor of acute kidney injury and mortality in a critically ill patient population.

Low serum 25-hydroxyvitamin D levels and acute kidney injury in the critically ill

Given the importance of inflammation in acute kidney injury and the relationship between vitamin D and inflammation, we sought to elucidate the effect of vitamin D status on acute kidney injury. We hypothesized that deficiency in 25-hydroxyvitamin D (25(OH)D) prior to hospital admission would be associated with acute kidney injury in the critically ill.

Malnutrition and inflammation in acute kidney injury due to earthquake-related crush syndrome

BackgroundMalnutrition and inflammation are common and serious complications in patients with acute kidney injury (AKI). However, the profile of these complications in patients with AKI caused by crush syndrome (CS) remains unclear. This study describes the clinical characteristics of malnutrition and inflammation in patients with AKI and CS due to the Wenchuan earthquake.MethodsOne thousand and twelve victims and eighteen healthy adults were recruited to the study. They were divided into five groups: Group A was composed of victims without CS and AKI (904 cases); Group B was composed of patients with CS and AKI who haven't received renal replacement therapy (RRT) (57 cases); and Group C was composed of patients with CS and AKI receiving RRT (25 cases); Group D was composed of earthquake victims with AKI but without CS (26 cases); and Group E was composed of 18 healthy adult controls. The C-reactive protein (CRP), prealbumin, transferrin, interleukin-6 and TNF-α were measured and compared between Group E and 18 patients from Group C.ResultsThe results indicate that participants in Group C had the highest level of serum creatinine, blood urea nitrogen and uric acid. Approximately 92% of patients with CS who had RRT were suffering from hypoalbuminemia. The interleukin-6 and CRP levels were significantly higher in patients with CS AKI receiving RRT than in the control group. Patients in Group C received the highest dosages of albumin, plasma or red blood cell transfusions. One patient in Group C died during treatment.ConclusionsMalnutrition and inflammation was common in patients with earthquake-related CS and had a negative impact on the prognosis of these subjects. The results of this study indicate that the use of RRT, intensive nutritional supplementation and transfusion alleviated the degree of malnutrition and inflammation in hemodialysis patients with crush syndrome.

Assessment of arterial stiffness, oxidative stress and inflammation in acute kidney injury

BackgroundIt is well know that arterial stiffness, oxidative stress and inflammation are features of chronic kidney disease. The arterial changes have a multitude of potential interconnected causes including endothelial dysfunction, oxidative stress, inflammation, atherosclerosis and vascular calcification. There is evidence that arterial stiffness becomes progressively worse as CKD progresses. The contribution of the biochemical changes of uremic toxicity to arterial stiffness is less clear. The aim of this study is to elucidate the vascular changes in acute kidney injury. We hypothesise that arterial stiffness will be increased during acute kidney injury and this will return to normal after kidney function recovers.Methods/DesignOne hundred and forty four patients with acute kidney injury defined as an acute increase in serum creatinine to > 133 μmol/l or urea > 14.3 mmol/l or urine output < 410 ml/day will be recruited. Baseline measures of aortic pulse wave velocity, augmentation index, and brachial and central blood pressure will be recorded along with blood measures for oxidative stress and inflammation. Repeat measures will be taken at six and 12 months after the onset of the acute kidney injury.DiscussionThe role and contribution of the biochemical changes to arterial stiffness in the acute phase of kidney disease is not known. This study will primarily assess the time course changes in pulse wave velocity from the onset of acute kidney injury and after recovery. In addition it will assess augmentation index, central blood pressure and oxidative stress and inflammation. This may shed light on the contribution of biochemical kidney toxins on arterial stiffness in both acute kidney injury and chronic kidney disease.Trial RegistrationACTRN 12609000285257

Mediators of Inflammation in Acute Kidney Injury

Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is now believed to play a major role in the pathopathophysiology of AKI. It is hypothesized that in ischemia, sepsis and nephrotoxic models that the initial insult results in morphological and/or functional changes in vascular endothelial cells and/or in tubular epithelium. Then, leukocytes including neutrophils, macrophages, natural killer cells, and lymphocytes infiltrate into the injured kidneys. The injury induces the generation of inflammatory mediators like cytokines and chemokines by tubular and endothelial cells which contribute to the recruiting of leukocytes into the kidneys. Thus, inflammation has an important role in the initiation and extension phases of AKI. This review will focus on the mediators of inflammation contributing to the pathogenesis of AKI.