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BACKGROUND: Contrast-induced nephropathy (CIN) is a form of acute kidney injury (AKI) occurring in patients undergoing cardiac catheterization, such as coronary angiography (CAG) or percutaneous coronary intervention (PCI). Although the conventional criterion for CIN detection involves a rise in creatinine levels within 72 h after contrast media injection, several limitations exist in this definition. Up to now, various meta-analyses have been undertaken to assess the accuracy of different biomarkers of CIN prediction. However, the existing body of research lacks a cohesive overview. To address this gap, a comprehensive umbrella review was necessary to consolidate and summarize the outcomes of prior meta-analyses. This umbrella study aimed to offer a current, evidence-based understanding of the prognostic value of biomarkers in predicting CIN.
METHODS: A systematic search of international databases, including PubMed, Scopus, and Web of Science, from inception to December 12, 2023, was conducted to identify meta-analyses assessing biomarkers for CIN prediction. Our own meta-analysis was performed by extracting data from the included studies. Sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were assessed using Meta-Disc and CMA softwares.
RESULTS: Twelve studies were ultimately included in the umbrella review. The results revealed that neutrophil gelatinase-associated lipocalin (NGAL) exhibited the highest area under the curve (AUC), followed by cystatin-C, urinary kidney injury molecule-1 (uKIM-1), and brain natriuretic peptide (BNP) with AUCs of 0.91, 0.89, 0.85, and 0.80, respectively. NGAL also demonstrated the highest positive likelihood ratio [effect size (ES): 6.02, 95% CI 3.86-9.40], followed by cystatin-C, uKIM-1, and BNP [ES: 4.35 (95% CI 2.85-6.65), 3.58 (95% CI 2.75-4.66), and 2.85 (95% CI 2.13-3.82), respectively]. uKIM-1 and cystatin-C had the lowest negative likelihood ratio, followed by NGAL and BNP [ES: 0.25 (95% CI 0.17-0.37), ES: 0.25 (95% CI 0.13-0.50), ES: 0.26 (95% CI 0.17-0.41), and ES: 0.39 (0.28-0.53) respectively]. NGAL emerged as the biomarker with the highest diagnostic odds ratio for CIN, followed by cystatin-C, uKIM-1, BNP, gamma-glutamyl transferase, hypoalbuminemia, contrast media volume to creatinine clearance ratio, preprocedural hyperglycemia, red cell distribution width (RDW), hyperuricemia, neutrophil-to-lymphocyte ratio, C-reactive protein (CRP), high-sensitivity CRP, and low hematocrit (P < 0.05).
CONCLUSIONS: NGAL demonstrated superior diagnostic performance, exhibiting the highest AUC, positive likelihood ratio, and diagnostic odds ratio among biomarkers for CIN, followed by cystatin-C, and uKIM-1. These findings underscore the potential clinical utility of NGAL, cystatin-C and uKIM-1 in predicting and assessing CIN.

The prevalence of osteoporosis has been on the rise globally. With ageing populations, research has sought therapeutic solutions in novel areas. One such area is that of the adipokines. Current literature points to an important role for these chemical mediators in relation to bone metabolism. Well-established adipokines have been broadly reported upon. These include adiponectin and leptin. However, other novel adipokines such as visfatin, nesfatin-1, meteorin-like protein (Metrnl), apelin and lipocalin-2 are starting to be addressed pre-clinically and clinically. Adipokines hold pro-inflammatory and anti-inflammatory properties that influence the pathophysiology of various bone diseases. Omentin-1 and vaspin, two novel adipokines, share cardioprotective effects and play essential roles in bone metabolism. Studies have reported bone-protective effects of omentin-1, whilst others report negative associations between omentin-1 and bone mineral density. Lipocalin-2 is linked to poor bone microarchitecture in mice and is even suggested to mediate osteoporosis development from prolonged disuse. Nesfatin-1, an anorexigenic adipokine, has been known to preserve bone density. Animal studies have demonstrated that nesfatin-1 treatment limits bone loss and increases bone strength, suggesting exogenous use as a potential treatment for osteopenic disorders. Pre-clinical studies have shown adipokine apelin to have a role in bone metabolism, mediated by the enhancement of osteoblast genesis and the inhibition of programmed cell death. Although many investigations have reported conflicting findings, sufficient literature supports the notion that adipokines have a significant influence on the metabolism of bone. This review aims at highlighting the role of novel adipokines in osteoporosis while also discussing their potential for treating osteoporosis.

BACKGROUND: Studies have uncovered LCN2 as a marker of inflammation strongly related to obesity, insulin resistance, and abnormal glucose metabolism in humans, and is involved in vascular diseases, inflammatory diseases, and neurological diseases. In recent years, studies have shown that elevated levels of LCN2 have a strong association with diabetic retinopathy (DR), but the pathogenesis is unknown. Here, we reviewed the relevant literature and compiled the pathogenesis associated with LCN2-induced DR.
METHODS: We searched PubMed and Web of Science electronic databases using \"lipocalin-2, diabetic retinopathy, retinal degeneration, diabetic microangiopathies, diabetic neuropathy and inflammation\" as subject terms.
RESULTS: In diabetic retinal neuropathy, LCN2 causes impaired retinal photoreceptor function and retinal neurons; in retinal microangiopathy, LCN2 induces apoptosis of retinal vascular endothelial cells and promotes angiogenesis; in retinal inflammation, increased secretion of LCN2 recruits inflammatory cells and induces pro-inflammatory cytokines. Moreover, LCN2 has the potential as a biomarker for DR. Recent studies have shown that retinal damage can be attenuated by silencing LCN2, which may be associated with the inhibition of caspase-1-mediated pyroptosis, and LCN2 may be a new target for the treatment of DR.
CONCLUSIONS: In conclusion, LCN2, involved in the development of diabetic retinopathy, is a key factor in diabetic retinal microangiopathy, neurodegeneration, and retinal inflammation. LCN2 is likely to be a novel molecular target leading to DR, and a more in-depth study of the pathogenesis of DR caused by LCN2 may provide considerable benefits for clinical research and potential drug development.

Activated neutrophils release a range of inflammatory products that represent potential biomarkers, and there is interest in the prognostic value of these in acute coronary syndrome (ACS) patients. We conducted a systematic review to examine neutrophil-enriched biomarkers and the occurrence of major adverse cardiovascular events (MACE) in patients with ACS. We identified twenty-seven studies including 17,831 patients with ACS. The most studied biomarkers were neutrophil gelatinase-associated lipocalin (NGAL) and myeloperoxidase (MPO). Meta-analyses showed that elevated NGAL was associated with higher MACE rates (unadjusted risk ratio (RR) 1.52, 95% CI 1.12-2.06, p = 0.006) as were elevated MPO levels (unadjusted RR 1.61, 95% CI 1.22-2.13, p = 0.01). There was limited data suggesting that increased levels of calprotectin, proteinase-3 and double-stranded DNA were also associated with MACE. These results suggest that higher levels of neutrophil-enriched biomarkers may be predictive of MACE in patients with ACS, although higher-quality studies are needed to confirm these observations.

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.

The associations between lipocalin-2 (LCN2) with mild cognitive impairment (MCI) and dementia have gained growing interest. However, population-based studies have yielded inconsistent findings. Therefore, we conducted this essential systematic review and meta-analysis to analyze and summarize the existing population-based evidence.
PubMed, EMBASE, and Web of Science were systematically searched until Mar 18, 2022. Meta-analysis was performed to generate the standard mean difference (SMD) of peripheral blood and cerebrospinal fluid (CSF) LCN2. A qualitative review was performed to summarize the evidence from postmortem brain tissue studies.
In peripheral blood, the overall pooled results showed no significant difference in LCN2 across Alzheimer\'s disease (AD), MCI and control groups. Further subgroup analysis revealed higher serum LCN2 levels in AD compared to controls (SMD =1.28 [0.44;2.13], p = 0.003), while the difference remained insignificant in plasma (SMD =0.04 [-0.82;0.90], p = 0.931). Besides, peripheral blood LCN2 were higher in AD when age difference between AD and controls ≥ 4 years (SMD =1.21 [0.37;2.06], p = 0.005). In CSF, no differences were found in LCN2 across groups of AD, MCI and controls. However, CSF LCN2 was higher in vascular dementia (VaD) compared to controls (SMD =1.02 [0.17;1.87], p = 0.018), as well as compared to AD (SMD =1.19 [0.58;1.80], p < 0.001). Qualitative analysis supported that LCN2 was increased in the brain tissue of AD-related areas, especially in astrocytes and microglia; while LCN2 increased in infarct-related brain areas and over-expressed in astrocytes and macrophages in mixed dementia (MD).
The difference in peripheral blood LCN2 between AD and controls may be affected by the type of biofluid and age. No differences were found in CSF LCN2 across AD, MCI and controls groups. In contrast, CSF LCN2 was elevated in VaD patients. Moreover, LCN2 was increased in AD-related brain areas and cells in AD, while in infarcts-related brain areas and cells in MD.

BACKGROUND: Protein neutrophil gelatinase-associated lipocalin (NGAL) has been associated with kidney injury and inflammatory conditions. In particular, several studies have found an association between maternal blood and urine levels and the development of pre-eclampsia.
OBJECTIVE: To examine whether maternal blood and urine levels of NGAL are good predictors of pre-eclampsia.
METHODS: The authors searched MEDLINE databases via PubMed, Embase, Scopus, Scielo, Google Scholar, PROSPERO International Prospective Register of Systematic Reviews, and the Cochrane Central Register of Controlled Trials.
METHODS: The authors included case-control observational clinical studies comparing protein levels of NGAL in serum and urine in women with pre-eclampsia with uncomplicated pregnancies. Only studies where the collection of blood or urine was peformed before the occurrence of pre-eclampsia were selected.
METHODS: The primary outcome was the difference in NGAL levels in blood or urine between women with and without pre-eclampsia.
RESULTS: Seven studies in total were included: five studies measuring NGAL in blood and two in urine. Regarding the serum studies, 315 patients were included as cases and 540 as controls. Higher NGAL in maternal blood during all three trimesters together was associated with pre-eclampsia; the standardized mean difference was 1.15 ng/mL (95% confidence interval, 0.92-1.39; P < 0.01). Regarding the urine studies, 39 patients were included as cases and 220 as controls. There was no statistically significant difference between patients with pre-eclampsia and controls regarding urine NGAL.
CONCLUSIONS: NGAL in maternal blood is higher in patients who later develop pre-eclampsia compared with controls and could be used as a potential predicting test in the routine clinical setting.

Severity of acute kidney injury (AKI) confers higher odds of mortality. Timely recognition and early initiation of preventive measures may help mitigate the injury further. Novel biomarkers may aid in the early detection of AKI. The utility of these biomarkers across various clinical settings in children has not been evaluated systematically.
To synthesize the currently available evidence on different novel biomarkers for the early diagnosis of AKI in pediatric patients.
We searched four electronic databases (PubMed, Web of Science, Embase, and Cochrane Library) for studies published between 2004 and May 2022.
Cohort and cross-sectional studies evaluating the diagnostic performance of biomarkers in predicting AKI in children were included.
Participants in the study included children (aged less than 18 years) at risk of AKI.
We used the QUADAS-2 tool for the quality assessment of the included studies. The area under the receiver operating characteristics (AUROC) was meta-analyzed using the random-effect inverse-variance method. Pooled sensitivity and specificity were generated using the hierarchical summary receiver operating characteristic (HSROC) model.
We included 92 studies evaluating 13,097 participants. Urinary NGAL and serum cystatin C were the two most studied biomarkers, with summary AUROC of 0.82 (0.77-0.86) and 0.80 (0.76-0.85), respectively. Among others, urine TIMP-2*IGFBP7, L-FABP, and IL-18 showed fair to good predicting ability for AKI. We observed good diagnostic performance for predicting severe AKI by urine L-FABP, NGAL, and serum cystatin C.
Limitations were significant heterogeneity and lack of well-defined cutoff value for various biomarkers.
Urine NGAL, L-FABP, TIMP-2*IGFBP7, and cystatin C showed satisfactory diagnostic accuracy in the early prediction of AKI. To further improve the performance of biomarkers, they need to be integrated with other risk stratification models.
PROSPERO (CRD42021222698). A higher resolution version of the Graphical abstract is available as \"Supplementary information\".

Several biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI.
In this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence.
We identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1-25.9), urinary NGAL (DOR 13.8, 95% CI 10.2-18.8), and serum NGAL (DOR 12.6, 95% CI 9.3-17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively.
Biomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients. Trial registration CRD42020207883 , October 06, 2020.