舒尼替尼治疗恶性胰岛细胞瘤疗效初探

恶性胰岛细胞瘤是一种少见但治疗效果欠佳的神经内分泌肿瘤.舒尼替尼作为新一代的酪氨酸激酶抑制剂,已被证实对于恶性胰岛细胞瘤具备较好的疗效.

Abstract：

Malignant islet cell tumor, a rare type of neuroendocrine carcinoma, biologically behaves in an aggressive way and is difficulty to be treated. Sunitinib malate, a novel tyrosine kinase inhibitor, demonstrates a high efficacy in treating malignant islet cell tumor as shown by promising results in recent trials.     

舒尼替尼对小鼠晚期乳腺癌模型的抑瘤作用

目的探讨舒尼替尼能否替代传统化疗成为晚期乳腺癌的一种治疗手段,或是与传统化疗结合能否提高疗效。方法建立荷4T1乳腺癌小鼠模型,分别给予舒尼替尼、多西他赛及两种药物联合治疗,用EGF荧光探针标记种植瘤,比较4组间种植瘤荧光密度值、双肺转移灶数目。结果所有药物干预组小鼠种植瘤体积及荧光密度值较对照组减低,联合组与多西他赛组种植瘤体积均小于舒尼替尼组。舒尼替尼组肺转移灶数目与对照组比较无统计学意义(P>0.05),多西他赛组及联合组均较舒尼替尼组及对照组转移灶数目少。结论舒尼替尼无论单药还是与传统化疗联合应用在晚期乳腺癌中均较传统化疗无明显优势。     

依维莫司和舒尼替尼联用提高抗胃癌活性的机制

目的探讨m TOR抑制剂依维莫司和受体酪氨酸激酶抑制剂(RTKIs)舒尼替尼在体内、体外试验中对胃癌细胞的增殖抑制及调控机制。方法实验分为空白对照组,依维莫司、舒尼替尼单独作用组和联合用药组。MTT法测定对人胃癌细胞NCI-N87的增殖抑制率,Western印迹方法检测体内外实验中各组p-AKT、p-S6的表达情况,酶联免疫吸附(ELISA)试剂盒测定人血管内皮生长因子(VEGF)的浓度;测量不同治疗组裸鼠移植瘤的体积,绘制肿瘤生长曲线。结果依维莫司抑制了体外胃癌细胞增殖,减少了p-S6的表达,降低了VEGF水平(均P<0.05),舒尼替尼的加入并没有产生有意义的变化。在体内试验中,两药联用更显著地抑制了肿瘤的生长;依维莫司阻止了p-S6的表达,引起p-AKT反馈性增加,与舒尼替尼联用部分抑制了AKT的超磷酸化;舒尼替尼诱导血清VEGF含量增加,两者共同作用时,血清VEGF水平则降至空白对照组之下(P<0.05)。结论体外胃癌细胞的增殖抑制是m TOR通路信号下调引起的,与舒尼替尼抑制血管生成机制并不相关。依维莫司和舒尼替尼联用能够更好地控制体内肿瘤的增长,这很可能是因为依维莫司阻碍了舒尼替尼诱导产生VEGF,提高了抗胃癌治疗效果。     

舒尼替尼治疗肝细胞癌的临床研究现状

舒尼替尼是一种口服小分子多靶点酪氨酸激酶抑制剂,具有抗血管生成和抗肿瘤活性。然而Ⅱ期临床试验显示其治疗肝细胞癌(HCC)有较高的药物相关死亡事件发生率,且客观应答率较低。近年一项Ⅲ期临床试验提示,舒尼替尼治疗进展期HCC的中位总体生存期显著短于多激酶抑制剂索拉非尼,因此舒尼替尼单药不被推荐用于治疗进展期HCC。一项正在进行的Ⅲ期临床试验拟比较舒尼替尼联合经动脉化疗栓塞术(TACE)与单用TACE治疗HCC的疗效,其结果将证实舒尼替尼是否可作为TACE治疗HCC的辅助手段。     

白黎芦醇对大鼠脑缺血再灌注损伤的保护作用

目的探讨白黎芦醇对大鼠脑缺血再灌注损伤的保护机制。方法随机选取64只SD大鼠分为假手术组、脑缺血再灌注组、低剂量组及高剂量组,于缺血2 h再灌注24 h进行神经功能缺损评分,并测定丙二醛(MDA)、超氧化物歧化酶(SOD)含量、脑梗死体积及脑含水量。结果四组的神经功能缺损评分、脑梗死体积及脑组织含水量由高到低排列为脑缺血再灌注组、低剂量组、高剂量组、假手术组(P<0.05);四组的大脑皮质、海马及血清中的MDA含量由高到低排列为脑缺血再灌注组、低剂量组、高剂量组、假手术组,SOD含量由低到高排列为脑缺血再灌注组、低剂量组、高剂量组、假手术组(P<0.05)。结论 白藜芦醇对脑组织再灌注损伤具有保护作用,可能的机制是清除自由基从而减少氧化损伤。     

白黎芦醇调节SIRT1表达研究的新进展

SIRT1是依赖烟酰胺腺嘌呤二核苷酸(NAD+)的脱乙酰基酶,在低等动物中延长寿命,预防与年龄相关的疾病,包括代谢紊乱。激活SIRT1能增强线粒体的功能、氧化代谢和抵消肥胖。白黎芦醇是非黄酮类多酚类,属于对苯代乙烯组,是一些植物为了应对伤害和真菌攻击自然产生的。因此,白黎芦醇激活SIRT1对与年龄相关的疾病和生理代谢有重要的意义。     

白黎芦醇体外对多房棘球蚴原头节和微囊的作用研究

目的 研究白藜芦醇(Resveratrol,RES)体外对多房棘球蚴原头节(Protoscoleces,PSCs)和微囊的作用效果,为多房棘球蚴病的临床用药提供新的依据.方法 PSCs体外经不同浓度(5、10、20、40、80、100、200和400 μmol/L)的RES作用7 d,采用台盼蓝染色观察其活力与形态变化...     

伊马替尼联合槲皮素对K562细胞增殖和凋亡协同作用的机制研究

目的:探讨槲皮素联合伊马替尼对K562细胞增殖的影响以及诱导凋亡的机制。方法:将不同浓度的槲皮素、伊马替尼单药和联合用药作用于K562细胞,绘制协同曲线。将0.25μmol/L伊马替尼与25μmol/L的槲皮素联合作用于K562细胞,通过细胞计数检测细胞增殖,流式细胞术检测细胞周期、线粒体跨膜电位的变化,蛋白质印迹法检测相关蛋白的表达。结果:0.25μmol/L伊马替尼联合25μmol/L槲皮素对K562细胞有明显的协同抑制生长和诱导凋亡作用。两药联合处理能降低K562细胞线粒体跨膜电位,使胱天蛋白酶(caspase)9和胱天蛋白酶3发生剪切,并明显下调B细胞淋巴瘤(Bcl)2样蛋白1(Bcl-xl)和髓样细胞白血病-1(Mcl-1)蛋白的表达。结论:伊马替尼与槲皮素协同抑制K562细胞生长并诱导细胞凋亡,其机制主要通过下调Bcl-xl以及Mcl-1蛋白的表达,从而激活线粒体凋亡途径来实现的。     

复方苦参注射液增加耐克唑替尼ALK阳性肺癌细胞H2228对克唑替尼的敏感性

目的探讨复方苦参注射液是否增加耐克唑替尼ALK阳性肺癌细胞H2228(H2228/CR)对克唑替尼的敏感性。方法采用CCK8方法观察复方苦参注射液、克唑替尼对H2228/CR细胞增殖的影响。取对数生长期H2228/CR细胞,加入不同浓度的复方苦参和克唑替尼,CCK8试剂测定各孔光吸收值(A),取平均值。计算药物作用72 h后的增殖抑制率。根据抑制率计算相应药物的IC50,然后选择适宜的复方苦参注射液浓度与克唑替尼联合,重复CCK8法,计算两药联合72 h后的细胞增殖抑制率及联合后克唑替尼的IC50,计算逆转倍数。结果复方苦参注射液、克唑替尼对H2228/CR细胞增殖具有抑制作用,该作用与浓度呈正相关。复方苦参注射液、克唑替尼对H2228/CR细胞的IC50分别为584.6μl/ml和3 426.3 nmol/L。复方苦参注射液联合不同浓度克唑替尼后对H2228/CR细胞较单用克唑替尼增殖抑制作用明显增强,联合用药后克唑替尼的IC50为494 nmol/L,逆转耐药倍数为6.93。H2228/CR对克唑替尼敏感性明显增强。结论相对单一应用克唑替尼易产生耐药性的缺点,二者联合运用可有效提高H2228/CR对克唑替尼敏感性。     

伊马替尼耐药机制及对策的研究进展

伊马替尼（Imatinib,STI571）是一种特异性强,高效酪氨酸激酶抑制剂。临床试验表明治疗慢性粒细胞白血病（CML）的疗效是干扰素的10倍。但是,该药在晚期或急变期CML平均使用10．5周后疗效明显下降,提示这些患者使用该药后发生了耐药。其发生机制可能为BCR-ABL酪氨酸激酶蛋白的浓度增加,mRNA的表达水平的上调,基因扩增或突变,多耐药基因1（multi drug resistance,mdr1）及其产物P-gP的过表达及其它机制。发生耐药后的主要对策为联合传统化疗药物和其他信号转导抑制剂或加大伊马替尼的剂量。     

H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence

Cellular senescence is a tumor-suppressive program that involves chromatin reorganization and specific changes in gene expression that trigger an irreversible cell-cycle arrest. Here we combine quantitative mass spectrometry, ChIP deep-sequencing, and functional studies to determine the role of histone modifications on chromatin structure and gene-expression alterations associated with senescence in primary human cells. We uncover distinct senescence-associated changes in histone-modification patterns consistent with a repressive chromatin environment and link the establishment of one of these patterns--loss of H3K4 methylation--to the retinoblastoma tumor suppressor and the H3K4 demethylases Jarid1a and Jarid1b. Our results show that Jarid1a/b-mediated H3K4 demethylation contributes to silencing of retinoblastoma target genes in senescent cells, suggesting a mechanism by which retinoblastoma triggers gene silencing. Therefore, we link the Jarid1a and Jarid1b demethylases to a tumor-suppressor network controlling cellular senescence.     

From the Cover: FGF2 is a target and a trigger of epigenetic mechanisms associated with differences in emotionality: Partnership with H3K9me3

Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety- and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes’ opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.Chromatin remodeling is a mediator of lasting neural changes in response to experience, such as exposure to stress and drugs of abuse (1–7). Indeed, the interaction of certain modified histones with specific gene promoters has been shown to be an important mechanism of experience-dependent neuroplasticity (8–13). Although numerous studies have examined the impact of the environment on neural epigenetic profiles, relatively few studies have focused on preexisting differences in epigenetic profiles as potential predisposing factors in emotional reactivity. Such studies require the availability of an animal model where difference in “temperament” or propensity for specific affective responses can be reliably predicted and altered. Our laboratory has generated such an animal model that captures vulnerability for “internalizing disorders” vs. “externalizing disorders.” Selectively bred high responder (bHR) rats exhibit greater responsiveness to novelty and to drug seeking behavior (externalizing behaviors), whereas selectively bred low responders (bLR) exhibit greater anxiety and depression-like responses (internalizing behaviors) (14, 15). These genetically bred phenotypes amplify behavioral traits observed in outbred animals (16–20).Several genes have been implicated in modifying these phenotypes, both in the bred and outbred lines (14). In particular, a key gene in stress regulation, the glucocorticoid receptor (GR) showed higher levels of mRNA expression in the hippocampus (HC) of outbred LRs relative to outbred HRs, and has been implicated in increased anxiety behavior in these animals. Thus, administration of a GR antagonist into the HC reduced anxiety behavior in outbred LR rats. Importantly, bLRs also exhibit significantly higher levels of hippocampal GR mRNA compared with bHRs, whereas the mineralocorticoid receptor (MR) showed no differences between the lines (17). Moreover, our mouse genetic studies have demonstrated that GR is an early-life modifier of emotional reactivity, with its overexpression before weaning enhancing anxiety throughout life (21). This then suggests that GR a critical molecular organizer of stable differences in affective reactivity.A countervailing modifier of anxiety behavior is the Fibroblast Growth Factor-2 (FGF2). This molecular organizer plays a critical role in brain development and hippocampal neurogenesis (22, 23). Moreover, FGF2 has been proposed as an endogenous anxiolytic and antidepressant that is depleted in the brain of depressed humans (24, 25). Its direct chronic administration was anxiolytic and antidepressant in rodents (25) and the silencing of endogenous hippocampal FGF2 using short-hairpin RNA increased anxiety-like behavior in outbred rats (26, 27). Our bLRs, which exhibit higher anxiety and depression behaviors, have lower basal levels of FGF2 mRNA in HC and nucleus accumbens (NAcc) (28, 29), and an environmental manipulation during adulthood that decreases anxiety behavior induces FGF2 expression selectively in these bLRs (30). Moreover, early-life FGF2 administration selectively decreases anxiety in bLRs throughout life (28).In the present study, we evaluated the basal levels of various modified histone proteins (H3 and H4) in the HC, amygdala, and NAcc in the bHR and bLR rats. We then focused on a repressive trimethylated histone protein H3 at lysine 9 (H3K9me3) which is one of the most widely studied repressed modified histones (31), and which showed reliable bHR vs. bLR differences. Using chromatin immunoprecipiation (ChIP) assays, we asked whether some of the basal variations in GR and FGF2 expression between the bred lines might be the result of differences in the association of this histone at their promoter. Finally, we asked whether manipulating FGF2 either via early-life administration or via virally mediated knockdown can modify the epigenetic patterns observed in the bred lines.     

MALAT1-mediated EZH2 Recruitment to the GFER Promoter Region Curbs Normal Hepatocyte Proliferation in Acute Liver Injury

Background and AimsThe goal of this study was to investigate the mechanism by which the long noncoding RNA MALAT1 inhibited hepatocyte proliferation in acute liver injury (ALI).MethodsLipopolysaccharide (LPS) was used to induce an ALI cellular model in HL7702 cells, in which lentivirus vectors containing MALAT1/EZH2/GFER overexpression or knockdown were introduced. A series of experiments were performed to determine their roles in liver injury, oxidative stress injury, and cell biological processes. The interaction of MALAT1 with EZH2 and enrichment of EZH2 and H3K27me3 in the GFER promoter region were identified. Rats were treated with MALAT1 knockdown or GFER overexpression before LPS induction to verify the results derived from the in vitro assay.ResultsMALAT1 levels were elevated and GFER levels were reduced in ALI patients and the LPS-induced cell model. MALAT1 knockdown or GFER overexpression suppressed cell apoptosis and oxidative stress injury induced cell proliferation, and reduced ALI. Functionally, MALAT1 interacted directly with EZH2 and increased the enrichment of EZH2 and H3K27me3 in the GFER promoter region to reduce GFER expression. Moreover, MALAT1/EZH2/GFER was activated the AMPK/mTOR signaling pathway.ConclusionOur study highlighted the inhibitory role of reduced MALAT1 in ALI through the modulation of EZH2-mediated GFER.     

Epigenetic histone H3 lysine 9 methylation in metabolic memory and inflammatory phenotype of vascular smooth muscle cells in diabetes

Diabetic patients continue to develop inflammation and vascular complications even after achieving glycemic control. This poorly understood "metabolic memory" phenomenon poses major challenges in treating diabetes. Recent studies demonstrate a link between epigenetic changes such as chromatin histone lysine methylation and gene expression. We hypothesized that H3 lysine-9 tri-methylation (H3K9me3), a key repressive and relatively stable epigenetic chromatin mark, may be involved in metabolic memory. This was tested in vascular smooth muscle cells (VSMC) derived from type 2 diabetic db/db mice. These cells exhibit a persistent atherogenic and inflammatory phenotype even after culture in vitro. ChIP assays showed that H3K9me3 levels were significantly decreased at the promoters of key inflammatory genes in cultured db/db VSMC relative to control db/+ cells. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase Suv39h1 were also reduced in db/db VSMC. Furthermore, db/db VSMC were hypersensitive to TNF-alpha inflammatory stimulus, which induced dramatic and sustained decreases in promoter H3K9me3 and Suv39h1 occupancy. Recruitment of corepressor HP1alpha was also reduced under these conditions in db/db cells. Overexpression of SUV39H1 in db/db VSMC reversed this diabetic phenotype. Conversely, gene silencing of SUV39H1 with shRNAs in normal human VSMC (HVSMC) increased inflammatory genes. HVSMC cultured in high glucose also showed increased inflammatory gene expression and decreased H3K9me3 at their promoters. These results demonstrate protective roles for H3K9me3 and Suv39h1 against the preactivated state of diabetic VSMC. Dysregulation of epigenetic histone modifications may be a major underlying mechanism for metabolic memory and sustained proinflammatory phenotype of diabetic cells.     

The plant homeodomain finger of RAG2 recognizes histone H3 methylated at both lysine-4 and arginine-2

Recombination activating gene (RAG) 1 and RAG2 together catalyze V(D)J gene rearrangement in lymphocytes as the first step in the assembly and maturation of antigen receptors. RAG2 contains a plant homeodomain (PHD) near its C terminus (RAG2-PHD) that recognizes histone H3 methylated at lysine 4 (H3K4me) and influences V(D)J recombination. We report here crystal structures of RAG2-PHD alone and complexed with five modified H3 peptides. Two aspects of RAG2-PHD are unique. First, in the absence of the modified peptide, a peptide N-terminal to RAG2-PHD occupies the substrate-binding site, which may reflect an autoregulatory mechanism. Second, in contrast to other H3K4me3-binding PHD domains, RAG2-PHD substitutes a carboxylate that interacts with arginine 2 (R2) with a Tyr, resulting in binding to H3K4me3 that is enhanced rather than inhibited by dimethylation of R2. Five residues involved in histone H3 recognition were found mutated in severe combined immunodeficiency (SCID) patients. Disruption of the RAG2-PHD structure appears to lead to the absence of T and B lymphocytes, whereas failure to bind H3K4me3 is linked to Omenn Syndrome. This work provides a molecular basis for chromatin-dependent gene recombination and presents a single protein domain that simultaneously recognizes two distinct histone modifications, revealing added complexity in the read-out of combinatorial histone modifications.     

麦冬皂苷D对大鼠心肌细胞缺氧复氧损伤的保护作用及机制研究

目的:探讨麦冬皂苷D对心肌细胞缺氧复氧损伤的保护作用及机制.方法:体外培养心肌细胞H9c2,实验分为心肌细胞未行任何干预的对照组、缺氧复氧组(H/R组)、缺氧复氧+麦冬皂苷D组(H/R+OpD组)、缺氧复氧+麦冬皂苷D+磷脂酰肌醇-3激酶(PI3K)过表达组(H/R+OpD+PI3K组)、缺氧复氧+麦冬皂苷D+pcDN...     

Neuronal necrosis is regulated by a conserved chromatin-modifying cascade

Neuronal necrosis induced by calcium overload causes devastating brain dysfunction in diseases such as stroke and brain trauma. It has been considered a stochastic event lacking genetic regulation, and pharmacological means to suppress neuronal necrosis are lacking. Using a Drosophila model of calcium overloading, we found JIL-1/mitogen- and stress-activated protein kinase 1/2 is a regulator of neuronal necrosis through phosphorylation of histone H3 serine 28 (H3S28ph). Further, we identified its downstream events including displacement of polycomb repressive complex 1 (PRC1) and activation of Trithorax (Trx). To test the role of JIL-1/PRC1/Trx cascade in mammals, we studied the necrosis induced by glutamate in rat cortical neuron cultures and rodent models of brain ischemia and found the cascade is activated in these conditions and inhibition of the cascade suppresses necrosis in vitro and in vivo. Together, our research demonstrates that neuronal necrosis is regulated by a chromatin-modifying cascade, and this discovery may provide potential therapeutic targets and biomarkers for neuronal necrosis.Glutamate-induced neuronal necrosis has been implicated in many devastating neurodegenerative diseases, including stroke, traumatic brain injury, epilepsy, and Alzheimer’s disease (1, 2). Ischemic stroke, for instance, is caused by a lack of oxygen and glucose in the brain, which leads to the excessive accumulation of glutamate in the extracellular space. Glutamate then activates N-methyl-d-aspartate (NMDA) receptors, which trigger calcium influx and a series of detrimental events, including production of nitric oxide (NO), activation of extracellular signal-regulated kinase (ERK1/2) and calpain, swelling of organelles, rupture of plasma membrane, and irreversible necrotic cell death in neurons (1, 3, 4). Calcium overload can activate the ERK pathway (5), and the translocation of activated ERK1/2 into the nucleus is required for their detrimental effect in neuronal necrosis (6), suggesting an unknown target in the nucleus may play a crucial role. In addition, chromatin modifications have been reported to associate with many pathological conditions of neurodegeneration (7). However, the molecular mechanism of chromatin alternations and their functional role remain to be investigated (8, 9).Previously, gain-of-function (GOF) mutants of the degenerin/epithelial Na⁺ channel (DEG/ENaC) family (deg-1 and mec-4) or of the acetylcholine receptor subunit gsa-1 (which results in the constitutive opening of these cation channels) were found to induce chronic neuronal necrosis in Caenorhabditis elegans (10, 11). However, genetic models of transient calcium overload are lacking, which hinders our understanding of the initial cellular responses to necrotic insults. Here, we describe the generation of a Drosophila model of transient necrosis and its application in studying the molecular mechanisms of neuronal necrosis. We discovered that necrosis was regulated by a chromatin-modifying cascade. Importantly, this regulatory mechanism was conserved in mammalian neuronal necrosis.     

Follow-Up Renal Assessment of Injury Long-Term After Acute Kidney Injury (FRAIL-AKI)

Background and objectives

Novel urinary kidney damage biomarkers detect AKI after cardiac surgery using cardiopulmonary bypass (CPB-AKI). Although there is growing focus on whether AKI leads to CKD, no studies have assessed whether novel urinary biomarkers remain elevated long term after CPB-AKI. We assessed whether there was clinical or biomarker evidence of long-term kidney injury in patients with CPB-AKI.

Design, setting, participants, & measurements

We performed a cross-sectional evaluation for signs of chronic kidney injury using both traditional measures and novel urinary biomarkers in a population of 372 potentially eligible children (119 AKI positive and 253 AKI negative) who underwent surgery using cardiopulmonary bypass for congenital heart disease at Cincinnati Children’s Hospital Medical Center between 2004 and 2007. A total of 51 patients (33 AKI positive and 18 AKI negative) agreed to long-term assessment. We also compared the urinary biomarker levels in these 51 patients with those in healthy controls of similar age.

Results

At long-term follow-up (mean duration±SD, 7±0.98 years), AKI-positive and AKI-negative patients had similarly normal assessments of kidney function by eGFR, proteinuria, and BP measurement. However, AKI-positive patients had higher urine concentrations of IL-18 (48.5 pg/ml versus 20.3 pg/ml [P=0.01] and 20.5 pg/ml [P<0.001]) and liver-type fatty acid–binding protein (L-FABP) (5.9 ng/ml versus 3.9 ng/ml [P=0.001] and 3.2 ng/ml [P<0.001]) than did AKI-negative patients and healthy controls.

Conclusions

Novel urinary biomarkers remain elevated 7 years after an episode of CPB-AKI in children. However, there is no conventional evidence of CKD in these children. These biomarkers may be a more sensitive marker of chronic kidney injury after CPB-AKI. Future studies are needed to understand the clinical relevance of persistent elevations in IL-18, kidney injury molecule-1, and L-FABP in assessments for potential long-term kidney consequences of CPB-AKI.