A major complication of type 1 diabetes is diabetic kidney disease (DKD). Albuminuria and impaired glomerular filtration rate are the main characteristics of DKD. Neutrophil gelatinase-associated lipocalin (NGAL) levels may rise even in the early stages of DKD, even in patients with normoalbuminuria. We present the first systematic review and meta-analysis examining the prognostic role of NGAL exclusively in pediatric patients with type 1 diabetes.

A search through major databases was carried out until September 24, 2024, investigating the prognostic role of NGAL in kidney injury in pediatric patients with type 1 diabetes. A p < 0.05 was considered statistically significant. A study quality assessment was conducted using the Newcastle-Ottawa Scale.

The standardized mean difference in urinary NGAL (uNGAL) levels between the type 1 diabetes group and healthy controls was statistically significant (SMD = 0.63, 95%CI [0.36,0.90]). A moderate positive relationship between uNGAL and ACR was identified (r = 0.53, 95 % CI [0.31-0.70]). The uNGAL revealed a high overall diagnostic accuracy (AUC = 0.881).

Urinary NGAL appears to be a valuable biomarker for early detection and understanding of DKD in individuals with type 1 diabetes. Future clinical studies should prioritize assessing the accuracy of NGAL in identifying kidney injury in pediatric patients with type 1 diabetes and the association of NGAL with traditional biomarkers in groups with similar characteristics.

Renal inflammatory diseases are a group of severe conditions marked by significant morbidity and mortality. Extracellular vesicles (EVs), as facilitators of intercellular communication, have been recognized as pivotal regulators of renal inflammatory diseases, significantly contributing to these conditions by modulating immune responses among other mechanisms. This review highlights the intricate mechanisms through which EVs modulate macrophage-kidney cell interactions by regulating macrophages, the principal immune cells within the renal milieu. This regulation subsequently influences the pathophysiology of renal inflammatory diseases such as acute kidney injury and chronic kidney disease. Furthermore, understanding these mechanisms offers novel opportunities to alleviate the severe consequences associated with renal inflammatory diseases. In addition, we summarize the therapeutic landscape based on EV-mediated macrophage regulatory mechanisms, highlighting the potential of EVs as biomarkers and therapeutic targets as well as the challenges and limitations of translating therapies into clinical practice.

In this study, we aimed to study the role of extracellular proteins as biomarkers associated with newly diagnosed Type 1 diabetes (NT1D) diagnosis and prognosis.

We retrieved and analyzed the GSE55098 microarray dataset from the Gene Expression Omnibus (GEO) database. Using R software, we screened out the extracellular protein-differentially expressed genes (EP-DEGs) through several protein-related databases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were applied to describe the role and function of these EP-DEGs. We used the STRING database to construct the interaction of proteins, Cytoscape software to visualize the protein-protein interaction (PPI) networks, and its plugin CytoHubba to identify the crucial genes between PPI networks. Finally, we used the comparative toxicogenomics database (CTD) to evaluate the connection between NT1D with the potential crucial genes and we validated our conclusions with another dataset (GSE33440) and some clinical samples.

We identified 422 DEGs and 122 EP-DEGs from a dataset that includes (12) NT1D patients compared with (10) healthy people. Protein digestion and absorption, toll-like receptor signaling, and T cell receptor signaling were the most meaningful pathways defined by KEGG enrichment analyses. We recognized nine important extracellular genes: GZMB, CCL4, TNF, MMP9, CCL5, IFNG, CXCL1, GNLY, and LCN2. CTD analyses showed that LCN2, IFNG, and TNF had higher levels in NT1D and hypoglycemia; while TNF, IFNG and MMP9 increased in hyperglycemia. Further verification showed that LCN2, MMP9, TNF and IFNG were elevated in NT1D patients.

The nine identified key extracellular genes, particularly LCN2, IFNG, TNF, and MMP9, may be potential diagnostic biomarkers for NT1D. Our findings provide new insights into the molecular mechanisms and novel therapeutic targets of NT1D.

Early identification of drug-induced acute kidney injury (AKI) is essential to prevent renal damage. The renal tubules are typically the first to exhibit damage, frequently accompanied by changes in renal tubular transporters. With this in mind, we have identified an endogenous substrate of the renal tubular transporters that may serve as a biomarker for early detection of drug-induced AKI. Using gentamicin- and vancomycin-induced AKI models, we found that traumatic acid (TA), an end metabolite, was rapidly increased in both AKI models. TA, a highly albumin-bound compound (96% to 100%), could not be filtered by the glomerulus and was predominantly eliminated by renal tubules via the OAT1, OAT3, OATP4C1, and P-gp transporters. Importantly, there is a correlation between elevated serum TA levels and reduced OAT1 and OAT3 levels. A clinical study showed that serum TA levels rose before an increase in serum creatinine in 13 out of 20 AKI patients in an intensive care unit setting. In addition, there was a notable rise in TA levels in the serum of individuals suffering from nephrotic syndrome, chronic renal failure, and acute renal failure. These results indicate that the decrease in renal tubular transporter expression during drug-induced AKI leads to an increase in the serum TA level, and the change in TA may serve as a monitor for renal tubular injury. Acute kidney injury (AKI) has a high clinical incidence, and if patients do not receive timely treatment and intervention, it can lead to severe consequences. During AKI, tubular damage is often the primary issue. Endogenous biomarkers of tubular damage are critical for the early diagnosis and treatment of AKI. However, there is currently a lack of reliable endogenous biomarkers for diagnosing tubular damage in clinical practice. Tubular secretion is primarily mediated by renal tubular transporters (channels), which are also impaired during tubular damage. Therefore, we aim to identify endogenous biomarkers of tubular damage from the perspective of renal tubular transporters, providing support for the early detection and intervention of AKI. TA is a substrate of multiple channels, including OAT1, OAT3, OATP4C1, and P-gp, and is primarily secreted by the renal tubules. In the early stages of rat AKI induced by GEN and VCA, serum TA levels are significantly elevated, occurring earlier than the rise in serum creatinine (SCr). Thus, TA is expected to become a potential endogenous biomarker for the early diagnosis of tubular damage.

Kidney diseases represent a diverse range of conditions that compromise renal function and structure which characterized by a progressive deterioration of kidney function, may ultimately necessitate dialysis or kidney transplantation as end-stage treatment options. This review explores the complex landscape of kidney diseases, highlighting the limitations of existing treatments and the pressing need for innovative strategies. The paper delves into the role of extracellular vesicles (EVs) as emerging biomarkers and therapeutic agents in the context of kidney pathophysiology. Urinary extracellular vesicles (uEVs), in particular, offer a non-invasive means of assessing renal injury and monitoring disease progression. Additionally, mesenchymal stem cell-derived EVs (MSC-EVs) are examined for their immunomodulatory and tissue repair capabilities, presenting a promising avenue for novel therapeutic interventions. And discusses the potential of engineering EVs to enhance their targeting and therapeutic efficacy. This paper systematically integrates the latest research findings and aims to provide a comprehensive overview of the role of EVs in kidney disease, providing cutting-edge insights into their potential as a diagnostic and therapeutic tool.

Type 1 diabetes mellitus (T1DM) is regarded as the most chronic autoimmune disease affecting children and adolescents that results from a destruction of pancreatic β-cell and leads to insulin insufficiency and persistent hyperglycemia (HG). Children and adolescents with T1DM are at an increased risk of developing microvascular complications, including diabetic nephropathy (DNE), diabetic retinopathy (DR), and diabetic neuropathy (DNU). The risk factors and prevalence of these complications differ greatly in pediatric studies. Screening for T1DM microvascular complications undergoes different stages and it is recommended to identify early symptoms and clinical signs. The identification of biomarkers in T1DM microvascular complications is needed to provide optimal treatment. Despite several studies on early biomarkers for DNE in children, the potential biomarkers for predicting DR and DNU have not been completely illustrated. This review fills this gap by identifying biomarkers of T1DM microvascular complications in children and adolescents through searches in the PubMed/Medline database.

Glomerular kidney diseases typically begin insidiously and can progress to end stage kidney failure. Early onset of therapy can slow down disease progression. Early diagnosis is required to ensure such timely therapy. The goal of our study was to evaluate protein biomarkers (BMs) for common nephropathies that have been described for children with Alport syndrome. Nineteen candidate BMs were determined by commercial ELISA in children with congenital anomalies of the kidneys and urogenital tract, inflammatory kidney injury, or diabetes mellitus. It is particularly essential to search for kidney disease BMs in children because they are a crucial target group that likely exhibits early disease stages and in which misleading diseases unrelated to the kidney are rare. Only minor differences in blood between affected individuals and controls were found. However, in urine, several biomarker candidates alone or in combination seemed to be promising indicators of renal injury in early disease stages. The BMs of highest sensitivity and specificity were collagen type XIII, hyaluronan-binding protein 2, and complement C4-binding protein. These proteins are unrelated to inflammation markers or to risk factors for and signs of renal failure. In conclusion, our study evaluated several strong candidates for screening for early stages of kidney diseases and can help to establish early nephroprotective regimens.

In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.

Extracellular vesicles (EVs) are membranous cargo particles that mediate intercellular communication. They are heterogeneous in size and mechanism of release, and found in all biological fluids. Since EV content is in relation to the originating cell type and to its physiopathological conditions, EVs are under study to understand organ physiology and pathology. In addition, EV surface cargo, or corona, can be influenced by the microenvironment, leading to the concept that EV-associated molecules can represent useful biomarkers for diseases. Recent studies also focus on the use of natural, engineered, or synthetic EVs for therapeutic purposes. This review highlights the role of EVs in kidney development, pediatric kidney diseases, including inherited disorders, and kidney transplantation. Although few studies exist, they have promising results and may guide researchers in this field. Main limitations, including the influence of age on EV analyses, are also discussed.

The primary function of the kidneys is to maintain systemic homeostasis (disruption of renal structure and function results in multilevel impairment of body function). Kidney diseases are characterized by a chronic, progressive course and may result in the development of chronic kidney disease (CKD). Evaluation of the composition of the proteome of urinary small extracellular vesicles (sEVs) as a so-called liquid biopsy is a promising new research direction. Knowing the composition of sEV could allow localization of cellular changes in specific sections of the nephron or the interstitial tissue before fixed changes, detectable only at an advanced stage of the disease, occur. Research is currently underway on the role of sEVs in the diagnosis and monitoring of many disease entities. Reports in the literature on the subject include: diabetic nephropathy, focal glomerulosclerosis in the course of glomerulopathies, renal fibrosis of various etiologies. Studies on pediatric patients are still few, involving piloting if small groups of patients without validation studies. Here, we review the literature addressing the use of sEV for diagnosis of the most common urinary disorders in children. We evaluate the clinical utility and define limitations of markers present in sEV as potential liquid biopsy.

Chronic kidney disease (CKD) poses a significant health burden worldwide. Especially, obesity-induced chronic kidney disease (OCKD) is associated with a lack of accuracy in disease diagnostic methods. The identification of reliable biomarkers for the early diagnosis and monitoring of CKD and OCKD is crucial for improving patient outcomes. Extracellular vesicles (EVs) have emerged as potential biomarkers in the context of CKD. In this review, we focused on the role of EVs as potential biomarkers in CKD and OCKD and developed a comprehensive list of EV membrane proteins that could aid in the diagnosis and monitoring of the disease. To assemble our list, we employed a multi-step strategy. Initially, we conducted a thorough review of the literature on EV protein biomarkers in kidney diseases. Additionally, we explored papers investigating circulating proteins as biomarkers in kidney diseases. To further refine our list, we utilized the EV database Vesiclepedia.org to evaluate the qualifications of each identified protein. Furthermore, we consulted the Human Protein Atlas to assess the localization of these candidates, with a particular focus on membrane proteins. By integrating the information from the reviewed literature, Vesiclepedia.org, and the Human Protein Atlas, we compiled a comprehensive list of potential EV membrane protein biomarkers for CKD and OCKD. Overall, our review underscores the potential of EVs as biomarkers in the field of CKD research, providing a foundation for future studies aimed at improving CKD and OCKD diagnosis and treatment.

Bacterial overgrowth is common for improperly stored urine. However, its effects on human urinary extracellular vesicles (uEVs) study had not been previously examined nor documented. This study investigated the presence of bacterial EVs (bEVs) contaminated in uEVs samples and their effects on uEVs study. Nanoscale uEVs were isolated from normal human urine immediately after collection (0-h) or after 25°C-storage with/without preservative (10 mM NaN3) for up to 24-h. Turbidity, bacterial count and total uEVs proteins abnormally increased in the 8-h and 24-h-stored urine without NaN3. NanoLC-ESI-LTQ-Orbitrap MS/MS identified 6-13 bacterial proteins in these contaminated uEVs samples. PCR also detected bacterial DNAs in these contaminated uEVs samples. Besides, uEVs derived from 8-h and 24-h urine without NaN3 induced macrophage activation (CD11b and phagocytosis) and secretion of cytokines (IFN-α, IL-8, and TGF-β) from macrophages and renal cells (HEK-293, HK-2, and MDCK). All of these effects induced by bacterial contamination were partially/completely prevented by NaN3. Interestingly, macrophage activation and cytokine secretion were also induced by bEVs purified from Escherichia coli. This study clearly shows evidence of bEVs contamination and their effects on human uEVs study when the urine samples were inappropriately stored, whereas NaN3 can partially/completely prevent such effects from the contaminated bEVs.

Diabetic nephropathy is one of the most serious microvascular complications of diabetes mellitus, with increasing prevalence and mortality. Currently, renal function is assessed clinically using albumin excretion rate and glomerular filtration rate. But before the appearance of micro-albumin, the glomerular structure has been severely damaged. Glomerular filtration rate based on serum creatinine is a certain underestimate of renal status. Early diagnosis of diabetic nephropathy has an important role in improving kidney function and delaying disease progression with drugs. There is an urgent need for biomarkers that can characterize the structural changes associated with the kidney. In this review, we focus on the early glomerular and tubular structural alterations, with a detailed description of the glomerular injury markers SMAD1 and Podocalyxin, and the tubular injury markers NGAL, Netrin-1, and L-FABP in the context of diabetic nephropathy. We have summarized the currently studied protein markers and performed bioprocess analysis. Also, a brief review of proteomic and scRNA-seq method in the search of diabetic nephropathy.