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PurposeThe aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI).MethodsThe RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724).Results364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75.ConclusionElevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein that is secreted mostly by immune cells such as neutrophils, macrophages, and dendritic cells. Its production is stimulated in response to inflammation. The concentrations of NGAL can be measured in plasma, urine, and biological fluids such as peritoneal effluent. NGAL is known mainly as a biomarker of acute kidney injury and is released after tubular damage and during renal regeneration processes. NGAL is also elevated in chronic kidney disease and dialysis patients. It may play a role as a predictor of the progression of renal function decreases with complications and mortality due to kidney failure. NGAL is also useful in the diagnostic processes of cardiovascular diseases. It is highly expressed in injured heart tissue and atherosclerostic plaque; its serum concentrations correlate with the severity of heart failure and coronary artery disease. NGAL increases inflammatory states and its levels rise in arterial hypertension, obesity, diabetes, and metabolic complications such as insulin resistance, and is also involved in carcinogenesis. In this review, we present the current knowledge on NGAL and its involvement in different pathologies, especially its role in renal and cardiovascular diseases.

Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for early diagnosis of acute kidney injury (AKI). However, the diagnostic value of NGAL for predicting AKI in sepsis patients is unclear. MEDLINE, EMBASE, and Cochrane Library databases were searched to identify research publications. Twelve studies from 9 countries including a total of 1582 patients, of whom 315 (19.9%) developed AKI, were included in the study; plasma NGAL levels were significantly higher in adult sepsis patients with AKI than in those without AKI (mean difference, 274.65; 95% confidence interval [CI], 106.16-443.15; I2 = 94%). Urine NGAL levels were not significantly different. The diagnostic odds ratio of plasma NGAL for predicting AKI in sepsis patients was 6.64 (95% CI, 3.80-11.58). The diagnostic accuracy of plasma NGAL was 0.881 (95% CI, 0.819-0.923) for sensitivity, 0.474 (95% CI, 0.367-0.582) for specificity, 0.216 (95% CI, 0.177-0.261) for positive predictive value and 0.965 (95% CI, 0.945-0.977) for negative predictive value. Plasma NGAL has a high sensitivity and a high negative predictive value for detection of AKI in adult sepsis patients. However, its low specificity and low positive predictive value could limit its clinical utility. The usefulness of urine NGAL was not revealed in this study.

In its early stages, symptoms of chronic kidney disease (CKD) are usually not apparent. Significant reduction of the kidney function is the first obvious sign of disease. If diagnosed early (stages 1 to 3), the progression of CKD can be altered and complications reduced. In stages 4 and 5 extensive kidney damage is observed, which usually results in end-stage renal failure. Currently, the diagnosis of CKD is made usually on the levels of blood urea and serum creatinine (sCr), however, sCr has been shown to be lacking high predictive value. Due to the development of genomics, epigenetics, transcriptomics, proteomics, and metabolomics, the introduction of novel techniques will allow for the identification of novel biomarkers in renal diseases. This review presents some new possible biomarkers in the diagnosis of CKD and in the prediction of outcome, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), uromodulin, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), miRNA, ncRNA, and lincRNA biomarkers and proteomic and metabolomic biomarkers. Complicated pathomechanisms of CKD development and progression require not a single marker but their combination in order to mirror all types of alterations occurring in the course of this disease. It seems that in the not so distant future, conventional markers may be exchanged for new ones, however, confirmation of their efficacy, sensitivity and specificity as well as the reduction of analysis costs are required.

Lipocalin-2 (LCN2) is a secreted glycoprotein linked to several physiological roles, including transporting hydrophobic ligands across cell membranes, modulating immune responses, maintaining iron homeostasis, and promoting epithelial cell differentiation. Although LNC2 is expressed at low levels in most human tissues, it is abundant in aggressive subtypes of cancer, including breast, pancreas, thyroid, ovarian, colon, and bile duct cancers. High levels of LCN2 have been associated with increased cell proliferation, angiogenesis, cell invasion, and metastasis. Moreover, LCN2 modulates the degradation, allosteric events, and enzymatic activity of matrix metalloprotease-9, a metalloprotease that promotes tumor cell invasion and metastasis. Hence, LCN2 has emerged as a potential therapeutic target against many cancer types. This review summarizes the most relevant findings regarding the expression, biological roles, and regulation of LCN2, as well as the proteins LCN2 interacts with in cancer. We also discuss the approaches to targeting LCN2 for cancer treatment that are currently under investigation, including the use of interference RNAs, antibodies, and gene editing.

Background Nephrotic syndrome is a common glomerular disorder. Treatment typically begins with corticosteroids, but patient response varies. Differentiating between steroid-sensitive nephrotic syndrome (SSNS) and steroid-resistant nephrotic syndrome (SRNS) early in the disease course is important, as SRNS is associated with a higher risk of poor long-term outcomes. Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker released in response to tubular injury, has emerged as a potential non-invasive marker for renal damage. Methods We conducted a systematic review and meta-analysis of studies reporting NGAL levels in SSNS and SRNS, based on the PRISMA guidelines. A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, ScienceDirect, and the WHO Virtual Health Library Regional. The statistical analysis was performed using a random-effects model to estimate the standardized mean difference (SMD) with a 95% confidence interval. Results A total of 16 studies were included. Meta-analyses revealed significantly higher urinary NGAL levels in both SSNS and SRNS patients compared to healthy controls. Urinary NGAL levels were significantly higher in SSNS and SRNS patients compared to healthy controls, with SMD = 0.78 (95% CI: 0.434–1.128, P  < .001) and SMD = 2.56 (95% CI: 1.152–3.971, P  < .001), respectively. Patients with SRNS had markedly higher urinary NGAL levels than those with SSNS (SMD = 1.889, 95% CI: 0.819–2.959, P  < .001). ROC analyses across several studies demonstrated moderate to strong discriminative ability of urinary NGAL in distinguishing between SRNS and SSNS. Conclusion Urinary NGAL demonstrated strong potential as a non-invasive biomarker for distinguishing between SRNS and SSNS, supporting its clinical utility in early diagnosis, risk stratification, and management.

Purpose Early diagnosis of acute kidney injury (AKI) remains a major challenge. We developed and validated AKI prediction models in adult ICU patients and made these models available via an online prognostic calculator. We compared predictive performance against serum neutrophil gelatinase-associated lipocalin (NGAL) levels at ICU admission. Methods Analysis of the large multicenter EPaNIC database. Model development ( n  = 2123) and validation ( n  = 2367) were based on clinical information available (1) before and (2) upon ICU admission, (3) after 1 day in ICU and (4) including additional monitoring data from the first 24 h. The primary outcome was a comparison of the predictive performance between models and NGAL for the development of any AKI (AKI-123) and AKI stages 2 or 3 (AKI-23) during the first week of ICU stay. Results Validation cohort prevalence was 29% for AKI-123 and 15% for AKI-23. The AKI-123 model before ICU admission included age, baseline serum creatinine, diabetes and type of admission (medical/surgical, emergency/planned) and had an AUC of 0.75 (95% CI 0.75–0.75). The AKI-23 model additionally included height and weight (AUC 0.77 (95% CI 0.77–0.77)). Performance consistently improved with progressive data availability to AUCs of 0.82 (95% CI 0.82–0.82) for AKI-123 and 0.84 (95% CI 0.83–0.84) for AKI-23 after 24 h. NGAL was less discriminant with AUCs of 0.74 (95% CI 0.74–0.74) for AKI-123 and 0.79 (95% CI 0.79–0.79) for AKI-23. Conclusions AKI can be predicted early with models that only use routinely collected clinical information and outperform NGAL measured at ICU admission. The AKI-123 models are available at http://akipredictor.com/ . Trial registration Clinical Trials.gov NCT00512122

Acute kidney injury (AKI) is a common complication in critically ill patients in the intensive settings with increased risks of short- and long-term complications and mortality. AKI is also associated with an increased length of stay in intensive care units (ICU) and worse kidney function recovery at hospital discharge. The management of AKI is one of the major challenges for nephrologists and intensivists overall for its early diagnosis. The current KDIGO criteria used to define AKI include the serum creatinine and urinary output that are neither sensitive nor specific markers of kidney function, since they can be altered only after hours from the kidney injury. In order to allow an early AKI detection, in the last years, several studies focused on the identification of new biomarkers. Among all these markers, urinary insulin-like growth factor-binding protein (IGFBP-7) and tissue inhibitor of metalloproteinase (TIMP-2) have been proven as the best-performing and have been proposed as a predictive tool for the AKI detection in the critical settings in order to perform an early diagnosis. Patients undergoing major surgery, cardiac surgery, those with hemodynamic instability or those with sepsis are believed to be the top priority patient populations for the biomarker test. In this view, the urinary [TIMP-2] x [IGFBP-7] becomes an important tool for the early detection of patients at high risk for AKI and its integration with the local ICU experience has to provide a multidisciplinary management of AKI with the institution of a rapid response team in order to assess patients and customize AKI management.

Kidney transplantation is the best option for end-stage chronic kidney disease. Transplant viability is conditioned by drugs’ nephrotoxicity, ischemia–reperfusion damage, or acute rejection. An approach to improve graft survival is the identification of post-transplant renal function prognostic biomarkers. Our objective was to study three early kidney damage biomarkers (N-acetyl-d-glucosaminidase, NAG; neutrophil gelatinase-associated lipocalin, NGAL; and kidney injury molecule-1, KIM-1) in the initial period after transplantation and to identify possible correlations with main complications. We analysed those biomarkers in urine samples from 70 kidney transplant patients. Samples were taken on days 1, 3, 5, and 7 after intervention, as well as on the day that renal function stabilised (based on serum creatinine). During the first week after transplant, renal function improved based on serum creatinine evolution. However, increasing levels of biomarkers at different times during that first week could indicate tubular damage or other renal pathology. A relationship was found between NGAL values in the first week after transplantation and delayed graft function. In addition, higher NAG and NGAL, and lower KIM-1 values predicted a longer renal function stabilisation time. Therefore, urinary NAG, NGAL, and KIM-1 could constitute a predictive tool for kidney transplant complications, contributing to improve graft survival rates.

A prompt diagnosis of urinary tract infection (UTI) is necessary to minimize its symptoms and limit sequelae. The current UTI screening by urine test strip analysis and microscopic examination has suboptimal diagnostic accuracy. A definitive diagnosis of UTI by urine culture takes two to three days for the results. These limitations necessitate a need for better biomarkers for the diagnosis and subsequent management of UTI in children. Here, we review the value of currently available UTI biomarkers and highlight the potential of emerging biomarkers that can facilitate a more rapid and accurate UTI diagnosis. Of the newer UTI biomarkers, the most promising are blood procalcitonin (PCT) and urinary neutrophil gelatinase-associated lipocalin (NGAL). PCT can provide diagnostic benefits and should be considered in patients who have a blood test for other reasons. NGAL, which is on the threshold of clinical care, needs more research to address its scope and utilization, including point-of-care application. Employment of these and other biomarkers may ultimately improve UTI diagnosis, guide UTI therapy, reduce antibiotic use, and mitigate UTI complications. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information