Urinary L-FABP and its combination with urinary NGAL in early diagnosis of acute kidney injury after cardiac surgery in adult patients

Background/Aim: The early detection of acute kidney injury (AKI) may be become possible by several promising early biomarkers which may facilitate the early detection, differentiation and prognosis prediction of AKI. In this study, we investigated the value of urinary liver-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL) and their combination in predicting the occurrence and the severity of AKI following cardiac surgery.

Methods: We prospectively followed 109 patients undergoing open heart surgery and identified 26 that developed AKI, defined as an increase in serum creatinine of ≥0.3?mg/dl or ≥150% of baseline creatinine. Serum creatinine (SCr), urinary L-FABP, and NGAL corrected by urine creatinine were tested pre-operation, at 0 hour and 2 hours post-operation. Each marker was assessed at each time point between patients with and without AKI. Receiver operating characteristic (ROC) curves and area under curves (AUC) were used to evaluate the diagnostic accuracy of urinary L-FABP, NGAL and their combination for predicting AKI.

Results: Patients were aged 63.0?±?11.3 years, 66.1% were male and baseline SCr was 70.5?±?19.1 umol/L. Of 109 patients, 26(23.9%) developed AKI (AKIN stage I, II and III were 46.2%, 34.6% and 19.2% separately). The levels of urinary L-FABP and NGAL were significantly higher in AKI patients than non-AKI patients at 0 hour and 2 hours postoperative. AUCs for L-FABP was 0.844 (sensitivity (ST) 0.846, specificity (SP) 0.819, cut-off (CO) 2226.50 μg/g Ucr) at 0 hours and 0.832 at 2 hours (ST 0.808, SP 0.747, CO 673.09 μg/g Ucr) while 0.866 for NGAL at 0 hours (ST 0.769, SP 0.819, CO 131.12 μg/g Ucr) and 0.871 at 2 hours (ST 0.808, SP 0.831, CO 33.73 μg/g Ucr) to predict AKI occurrence. Using a combination of L-FABP and NGAL analyzed at the same timepoint as above, we were able to obtain an AUC of 0.911–0.927, p < 0.001. Similar AUCs of 0.81–0.87 were found to predict AKI stage II–III.

Conclusions: Urinary L-FABP and NGAL increased at an early stage after cardiac surgery. The combination of the two biomarkers enhanced the accuracy of the early detection of postoperative AKI after cardiac surgery before a rise in SCr.     

心脏术后急性肾损伤的研究进展

急性肾损伤（Acute Kidney Injury,AKI）是心脏术后较常见且较严重的并发症,明显增加患者的住院费用,并且增加手术死亡率。研究发现术前肾功能不全、糖尿病、及外周血管疾病等是术后AKI的危险因素。最新的研究发现一些新的生物学标准物可以为我们早期诊断心脏术后AKI的发生的提供帮助。而一旦出现AKI,选择适当药物治疗和肾脏替代治疗,可以保护肾功能,改善AKI患者的预后。     

Novel biomarkers for post-contrast acute kidney injury identified from long non-coding RNA expression profiles

Background: Post-contrast acute kidney injury (PC-AKI) is a severe complication of cardiac catheterization. Emerging evidence indicated that long non-coding RNAs (lncRNAs) could serve as biomarkers for various diseases. However, the lncRNA expression profile and potential biomarkers in PC-AKI remain unclear. This study aimed to investigate novel lncRNA biomarkers for the early detection of PC-AKI.Methods: lncRNA profile in the kidney tissues of PC-AKI rats was evaluated through RNA sequencing. Potential lncRNA biomarkers were identified through human-rat homology analysis, kidney and blood filtering in rats and verified in 112 clinical samples. The expression patterns of the candidate lncRNAs were detected in HK-2 cells and rat models to evaluate their potential for early detection.Results: In total, 357 lncRNAs were found to be differentially expressed in PC-AKI. We identified lnc-HILPDA and lnc-PRND were conservative and remarkably upregulated in both kidneys and blood from rats and the blood of PC-AKI patients; these lncRNAs can precisely distinguish PC-AKI patients (area under the curve (AUC) values of 0.885 and 0.875, respectively). The combination of these two lncRNAs exhibited improved accuracy for predicting PC-AKI, with 100% sensitivity and 83.93% specificity. Time-course experiments showed that the significant difference was first noted in the blood of PC-AKI rats at 12 h for lnc-HILPDA and 24 h for lnc-PRND.Conclusion: Our study revealed that lnc-HILPDA and lnc-PRND may serve as the novel biomarkers for early detection and profoundly affect the clinical stratification and strategy guidance of PC-AKI.     

Serum and urinary biomarkers for early detection of acute kidney injury following Hypnale spp. envenoming

BackgroundHump-nosed pit viper (HNV; Hypnale spp.) bites account for most venomous snakebites in Sri Lanka. Acute kidney injury (AKI) is the most serious systemic manifestation (1–10%) following HNV envenoming. We aimed to identify the value of functional and injury biomarkers in predicting the development of AKI early following HNV bites.MethodsWe conducted a prospective cohort study of patients with confirmed HNV envenoming presenting to two large tertiary care hospitals in Sri Lanka. Demographics, bite details, clinical effects, complications and treatment data were collected prospectively. Blood and urine samples were collected from patients for coagulation and renal biomarker assays on admission, at 0-4h, 4-8h, 8-16h and 16-24h post-bite and daily until discharge. Follow-up samples were obtained 1 and 3 months post-discharge. Creatinine (sCr) and Cystatin C (sCysC) were measured in serum and kidney injury molecule-1 (uKIM-1), clusterin (uClu), albumin (uAlb), β2-microglobulin (uβ2M), cystatin C (uCysC), neutrophil gelatinase associated lipocalin (uNGAL), osteopontin (uOPN) and trefoil factor-3 (uTFF-3) were measured in urine. Definite HNV bites were based on serum venom specific enzyme immunoassay. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to stage AKI. Two patients had chronic kidney disease at 3 month follow-up, both with pre-existing abnormal sCr, and one developed AKI following HNV envenoming.ResultsThere were 52 patients with confirmed HNV envenoming; median age 48y (Interquartile range [IQR]:40-59y) and 29 (56%) were male. Median time to admission was 1.87h (IQR:1–2.75h). Twelve patients (23%) developed AKI (AKI stage 1 = 7, AKI stage 2 = 1, AKI stage 3 = 4). Levels of five novel biomarkers, the functional marker serum Cystatin C and the damage markers urinary NGAL, cystatin C, β2-microglobulin and clusterin, were elevated in patients who developed moderate/severe acute kidney injury. sCysC performed the best at 0–4 h post-bite in predicting moderate to severe AKI (AUC-ROC 0.95;95%CI:0.85–1.0) and no biomarker performed better than sCr at later time points.ConclusionssCysC appears to be a better marker than sCr for early prediction of moderate to severe AKI following HNV envenoming.     

基质金属蛋白酶与体外循环肺损伤研究进展

肺泡 毛细血管基底膜损伤是体外循环 (CPB)术后肺损伤发生和发展的主要病理过程 ,基质金属蛋白酶 (MMPs)可能通过降解细胞外基质、调节细胞因子而参与CPB所致肺损伤的发生 ,研究MMPs在CPB肺损伤中的作用机制 ,对于防治CPB术后肺损伤的发生和发展具有重要意义     

Noncoding RNAs in acute kidney injury

Acute kidney injury (AKI), caused by various stimuli including ischemia reperfusion, nephrotoxic insult, and sepsis, is characterized by abrupt decline of kidney function. Till now, the molecular mechanisms for AKI have not been fully explored and the effective therapies are still lacking. Noncoding RNAs (ncRNAs), a group of biomolecules function at RNA level, are involved in a wide range of physiopathological processes including AKI. MicroRNAs (miRNAs) are the most extensively studied ncRNAs in AKI. Evidence indicated that miRNAs are altered significantly in various types of AKI. Gain-and-loss-of-function studies demonstrated that miRNAs, such as miR-24, miR-126, miR-494, and miR-687, may bind to the 3′-untranslated region of their target genes to regulate inflammation, programmed cell death, and cell cycle in the injury and repair stages of AKI, indicating their therapeutic potential in AKI. In contrast, functions of long noncoding RNAs and circular RNAs in AKI are hot topics but still largely unknown. Additionally, ncRNAs packaged in exosome can be detected in circulation and urine, they may serve as specific biomarkers for AKI. This review summarized the alteration and functional role of ncRNAs and their therapeutic potential in AKI.     

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage

Abstract

This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg^?1). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg^?1). Serum testosterone was only significantly decreased at 500 mg kg^?1 and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.     

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage

This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg^-1). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg^-1). Serum testosterone was only significantly decreased at 500 mg kg^-1 and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.     

Method used to establish a large animal model of drug-induced acute kidney injury

Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.     

Cystatin C,a novel urinary biomarker for sensitive detection of acute kidney injury during haemorrhagic fever with renal syndrome

To explore the value of cystatin C for evaluating acute kidney injury (AKI) in haemorrhagic fever with renal syndrome (HFRS), the concentrations of cystatin C in serum and urine samples from HFRS patients were determined. The serum and urinary cystatin C concentrations significantly increased in HFRS patients compared with normal controls (p?<?0.001). In the acute phase of HFRS, urinary cystatin C increased to higher levels than serum creatinine, especially in severe or critical cases in the oliguric stage. Furthermore, higher levels of urinary cystatin C in the acute phase positively correlated with increased severity of the subsequent kidney injury. In conclusion, urinary cystatin C is a more sensitive clinical marker for AKI in HFRS, which may enable us to initiate treatment measures as early as possible.     

A miniaturized immunoassay platform to measure neutrophil gelatinase-associated lipocalin (NGAL) for diagnosis of acute kidney injury

Abstract

In this study, we describe the development and evaluation of a slide-based immunoassay platform for the detection of neutrophil gelatinase associated-lipocalin (NGAL) in plasma and urine samples. The capture NGAL antibody was immobilized onto a microscope slide before an analysis of NGAL based on a sandwich immunoassay was further carried out. This assay system exhibited linearity between 50 to 1000?ng/ml of NGAL. The coefficients of variability (CVs) indicated good reproducibility and repeatability of the system. The levels of plasma NGAL measured by the slide-based system were highly correlated with those of ELISA, while this system over-predicted urine NGAL.     

Urinary proteomics: a tool to discover biomarkers of kidney diseases

There is intense interest in applying proteomics to urine analysis in order to promote a better understanding of kidney disease processes, develop new biomarkers for diagnosis and detect early factors that contribute to end–stage renal diseases. This interest creates numerous opportunities as well as challenges. To fulfill this task, proteomics requires, in its different stages of realization, various technological platforms with high sensitivity, high throughput and large automation ability. In this review, we will give an overview of promising proteomic methods that can be used for analyzing urinary proteome and detecting biomarkers for different kidney diseases. Furthermore, we will focus on the current status and future directions in investigating kidney diseases using urinary proteomics.     

Increase in urinary markers during the acute phase reflects the degree of chronic tubulointerstitial injury after ischemia-reperfusion renal injury

Context: Acute kidney injury (AKI) could lead to progressive chronic kidney disease (CKD). Objectives: To demonstrate that urinary markers in AKI are associated with the degree of persistent renal injury. Material and methods: Human L-FABP chromosomal transgenic (T_g) mice were subjected to ischemia-reperfusion (I/R) clamping renal pedicle for 20?min or 30?min. Kidneys were obtained at one and 40 days after I/R. Results: Urinary L-FABP, NGAL, Kim-1 and albumin levels increased during the acute phase and were significantly correlated with the degree of tubulointerstitial fibrosis during the chronic phase. Discussion and conclusion: These markers could detect higher risk of progression to CKD.     

HO-1 mitigates acute kidney injury and subsequent kidney-lung cross-talk

Abstract

Ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI), which contributes to the development of chronic kidney disease (CKD). IRI-induced AKI releases proinflammatory cytokines (e.g. IL-1β, TNF-α, IL-6) that induce a systemic inflammatory response, resulting in proinflammatory cells recruitment and remote organ damage. AKI is associated with poor outcomes, particularly when extrarenal complications or distant organ injuries occur. Acute lung injury (ALI) is a major remote organ dysfunction associated with AKI. Hence, kidney-lung cross-talk remains a clinical challenge, especially in critically ill population. The stress-responsive enzyme, heme oxygenase-1 (HO-1) is largely known to protect against renal IRI and may be preventively induced using hemin prior to renal insult. However, the use of hemin-induced HO-1 to prevent AKI-induced ALI remains poorly investigated. Mice received an intraperitoneal injection of hemin or sterile saline 1?day prior to surgery. Twenty-four hours later, mice underwent bilateral renal IRI for 26?min or sham surgery. After 4 or 24?h of reperfusion, mice were sacrificed. Hemin-induced HO-1 improved renal outcomes after IRI (i.e. fewer renal damage, renal inflammation, and oxidative stress). This protective effect was associated with a dampened systemic inflammation (i.e. IL-6 and KC). Subsequently, mitigated lung inflammation was found in hemin-treated mice (i.e. neutrophils influx and lung KC). The present study demonstrates that hemin-induced HO-1 controls the magnitude of renal IRI and the subsequent AKI-induced ALI. Therefore, targeting HO-1 represents a promising approach to prevent the impact of renal IRI on distant organs, such as lung.     

Circulating mitochondrial dysfunction as an early biomarker for contrast media-induced acute kidney injury in chronic kidney disease patients

Contrast-induced acute kidney injury (CI-AKI) is the common hospitalized acute kidney injury (AKI). However, the diagnosis by serum creatinine might not be early enough. Currently, the roles of circulating mitochondria in CI-AKI are still unclear. Since early detection is crucial for treatment, the association between circulating mitochondrial function and CI-AKI was tested as a potential biomarker for detection of CI-AKI. Twenty patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) were enrolled. Blood and urine samples were obtained at the time of PCI, and 6, 24, 48 and 72 h after PCI. Plasma and urine neutrophil gelatinase-associated lipocalin (NGAL) were measured. Oxidative stress, inflammation, mitochondrial function, mitochondrial dynamics and cell death were determined from peripheral blood mononuclear cells. Forty percent of patients developed AKI. Plasma NGAL levels increased after 24 h after receiving contrast media. Cellular and mitochondrial oxidative stress, mitochondrial dysfunction and decreased mitochondrial fusion occurred at 6 h following contrast media exposure. Subgroup of AKI had higher %necroptosis cells and TNF-α mRNA expression than subgroup without AKI. Collectively, circulating mitochondrial dysfunction could be an early predictive biomarker for CI-AKI in CKD patients receiving contrast media. These findings provide novel strategies to prevent CI-AKI according to its pathophysiology.     

人脐带间充质干细胞微囊减轻小鼠急性肾损伤的研究

目的探讨人脐带间充质干细胞（MSCs）源性细胞外囊泡Oct-4 mRNA对受损的肾小管上皮细胞修复的作用及相关机制。 方法将培养的缺氧损伤肾小管上皮细胞置于含有人脐带MSCs细胞外囊泡及不同对照培养液的培养腔室玻片上孵育48?h,应用BrdU及TUNEL染色,检测各组细胞增殖或凋亡情况。将急性肾损伤模型小鼠分为4组：空白组、EVs组、Oct-4过表达组、Oct-4低敲组。并按照分组分别注射磷酸盐缓冲液（Vehicle）,人脐带MSCs细胞外囊泡（EVs）,过表达Oct-4基因的人脐带MSCs细胞外囊泡（EVs?+?Oct-4）及敲除Oct-4基因的人脐带MSCs外囊泡（EVs-Oct-4）,并在注射48?h及2周后采血测肌酐（Crea）及尿素氮（BUN）,了解肾功能变化;对各组上述处理后的肾组织应用TUNEL与增殖细胞核抗原表达量检测各组肾脏细胞凋亡与增殖情况;通过Masson染色检测了各组肾脏纤维化程度;通过PCR探索肾损伤后肾组织细胞Snail基因的表达变化。数据分析采用方差分析和SNK-q检验。 结果EVs?+ Oct-4处理缺氧的肾小管上皮细胞48?h后,TUNEL染色显示具有最少的凋亡细胞数（0~1）/?HPF,BrdU显示有最多的增殖细胞（7±2）/HPF。EVs,EV-Oct-4以及Vehicle对体外缺氧肾小管上皮细胞的上述作用依次减弱（P?相似文献