Biomarker For Lupus Nephritis Research Articles

Serum Uric Acid Combined with Homocysteine as a Predictive Biomarker of Lupus Nephritis.

Serum uric acid (UA) and homocysteine (Hcy) are potential biomarkers of systemic lupus erythematosus (SLE). In this study, the expressions of UA and Hcy in SLE patients and the predictive value of these two parameters for lupus nephritis (LN) were studied. A total of 476 SLE patients were recruited to this case-control study, of which 176 SLE patients diagnosed with LN and 300 without LN. Serum UA and Hcy levels were analyzed. Multivariate logistic regression analysis was used to evaluate the relationship between serum UA and Hcy and LN. The receiver operating characteristic (ROC) curves were used to predict the role of combination of serum UA and Hcy in LN. We found that serum UA and Hcy levels in SLE patients with LN were significantly higher than those in controls (p<0.05). Multivariate logistic regressions showed that serum UA (OR+=+1.003, 95+% CI: 1.001-1.006, p+=+0.003), apolipoprotein B (Apo B) (OR+=+21.361, 95+% CI: 2.312-195.373, p+=+0.007) and Hcy (OR+=+1.042, 95+% CI: 1.011-1.080, p+=+0.014) were independent markers of LN. Combined serum UA and Hcy revealed a better result (AUC+=+0.718, 95+% CI: 0.670-0.676, p<0.001) in prediction of LN compared to that of the serum UA (AUC+=+0.710) and Hcy (AUC+=+0.657) independently. In conclusion, serum UA and Hcy could be predictive biomarkers of LN, and joint detection of serum UA and Hcy might be useful in the clinical setting.

Long noncoding RNAs (CTC-471J1.2, NeST) as epigenetic risk factors of active juvenile lupus nephritis: a case-control study

BackgroundMeasurement of the circulating levels of long-non-coding RNAs (lncRNAs) in lupus nephritis (LN) patients could dramatically explore more insights about the disease pathogenesis. Hence, we aimed to quantify the level of expression of CTC-471J1.2 and NeST in LN patients and to correlate it with the disease activity.MethodThis case-control study was conducted on a group of children with juvenile LN attending to Mansoura University Children’s Hospital (MUCH). Demographics, clinical, and laboratory findings were collected besides the measurement of lncRNAs by quantitative real-time PCR.ResultsThe expression level of lncRNAs-CTC-471J1.2 was significantly down-regulated in children with active LN versus inactive cases or controls. In contrast, the NeST was significantly up-regulated in active LN cases. A significant correlation was found between CTC-471J1.2 expression and LN activity parameters. Additionally, both lncRNAs showed a reasonable sensitivity and specificity in differentiation of active LN. A regression analysis model revealed that CTC-471J1.2 and NeST were independent predictors of active nephritis.ConclusionThe expression level of circulatory lncRNAs-CTC-471J1.2 and NeST can be used as sensitive and specific biomarkers for active LN. Furthermore, both could serve as predictors for nephritis activity.

Urinary metabolomic profiling of a cohort of Colombian patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune and multisystem disease with a high public health impact. Lupus nephritis (LN), commonly known as renal involvement in SLE, is associated with a poorer prognosis and increased rates of morbidity and mortality in patients with SLE. Identifying new urinary biomarkers that can be used for LN prognosis or diagnosis is essential and is part of current active research. In this study, we applied an untargeted metabolomics approach involving liquid and gas chromatography coupled with mass spectrometry to urine samples collected from 17 individuals with SLE and no kidney damage, 23 individuals with LN, and 10 clinically healthy controls (HCs) to identify differential metabolic profiles for SLE and LN. The data analysis revealed a differentially abundant metabolite expression profile for each study group, and those metabolites may act as potential differential biomarkers of SLE and LN. The differential metabolic pathways found between the LN and SLE patients with no kidney involvement included primary bile acid biosynthesis, branched-chain amino acid synthesis and degradation, pantothenate and coenzyme A biosynthesis, lysine degradation, and tryptophan metabolism. Receiver operating characteristic curve analysis revealed that monopalmitin, glycolic acid, and glutamic acid allowed for the differentiation of individuals with SLE and no kidney involvement and individuals with LN considering high confidence levels. While the results offer promise, it is important to recognize the significant influence of medications and other external factors on metabolomics studies. This impact has the potential to obscure differences in metabolic profiles, presenting a considerable challenge in the identification of disease biomarkers. Therefore, experimental validation should be conducted with a larger sample size to explore the diagnostic potential of the metabolites found as well as to examine how treatment and disease activity influence the identified chemical compounds. This will be crucial for refining the accuracy and effectiveness of using urine metabolomics for diagnosing and monitoring lupus and lupus nephritis.

Extracellular mitochondrial components as new biomarkers for lupus nephritis.

Major reason for mortality among systemic lupus erythematosus patients is renal failure due to the deposition of immune complexes in the glomeruli. Being a chronic disease with multiple relapses and remissions across the lifespan, it's important to know the degree of nephritis for diagnosis as well as the long-term clinical management of the patients. Currently, renal biopsy is being used as the gold standard to diagnose and define the stages of the disease. However, renal biopsy being invasive only provides a localized picture of nephritis, and has the risk of bleeding. Additionally, it is also cost-intensive. Hence, a reliable, non-invasive biomarker is required for lupus nephritis. This study has evaluated extracellular mitochondrial components, including cell-free mitochondria, and cell-free mitochondrial DNA as probable biomarkers of the degree of nephritis. Both showed a significant correlation with proteinuria and protein-creatinine ratio. Our study substantiates their usage as clinical biomarkers of nephritis upon their validation in a larger cohort of lupus nephritis patients and other forms of nephritis. Although the current data suggest using cell-free mitochondria as a biomarker of lupus nephritis is better than the cell-free mitochondrial DNA.

Advancing Point-of-Care Diagnosis: Digitalizing Combinatorial Biomarker Signals for Lupus Nephritis.

To improve the efficiency and patient coverage of the current healthcare system, user-friendly novel homecare devices are urgently needed. In this work, we developed a smartphone-based analyzing and reporting system (SBARS) for biomarker detection in lupus nephritis (LN). This system offers a cost-effective alternative to traditional, expensive large equipment in signal detection and quantification. This innovative approach involves using a portable and affordable microscopic reader to capture biomarker signals. Through smartphone-based image processing techniques, the intensity of each biomarker signal is analyzed. This system exhibited comparable performance to a commercial Genepix scanner in the detection of two potential novel biomarkers of LN, VISG4 and TNFRSF1b. Importantly, this smartphone-based analyzing and reporting system allows for discriminating LN patients with active renal disease from healthy controls with the area-under-the-curve (AUC) value = 0.9 for TNFRSF1b and 1.0 for VSIG4, respectively, indicating high predictive accuracy.

Noninvasive biomarkers for lupus nephritis.

Lupus nephritis (LN) is one of the most severe clinical manifestations of systemic lupus erythematosus (SLE). Notably, the clinical manifestations of LN are not always consistent with the histopathological findings. Therefore, the diagnosis and activity monitoring of this disease are challenging and largely depend on invasive renal biopsy. Renal biopsy has side effects and is associated with the risk of bleeding and infection. There is a growing interest in the development of novel noninvasive biomarkers for LN. In this review, we summarize most of the LN biomarkers discovered so far by correlating current knowledge with future perspectives. These biomarkers fundamentally reflect the biological processes of kidney damage and repair during disease. Furthermore, this review highlights the role of urinary cell phenotype detection in the diagnosis, monitoring, and treatment of LN and summarizes the limitations and countermeasures of this test.

Comprehensive analysis of lactate-related gene profiles and immune characteristics in lupus nephritis.

The most frequent cause of kidney damage in systemic lupus erythematosus (SLE) is lupus nephritis (LN), which is also a significant risk factor for morbidity and mortality. Lactate metabolism and protein lactylation might be related to the development of LN. However, there is still a lack of relative research to prove the hypothesis. Hence, this study was conducted to screen the lactate-related biomarkers for LN and analyze the underlying mechanism. To identify differentially expressed genes (DEGs) in the training set (GSE32591, GSE127797), we conducted a differential expression analysis (LN samples versus normal samples). Then, module genes were mined using WGCNA concerning LN. The overlapping of DEGs, critical module genes, and lactate-related genes (LRGs) was used to create the lactate-related differentially expressed genes (LR-DEGs). By using a machine-learning algorithm, ROC, and expression levels, biomarkers were discovered. We also carried out an immune infiltration study based on biomarkers and GSEA. A sum of 1259 DEGs was obtained between LN and normal groups. Then, 3800 module genes in reference to LN were procured. 19 LR-DEGs were screened out by the intersection of DEGs, key module genes, and LRGs. Moreover, 8 pivotal genes were acquired via two machine-learning algorithms. Subsequently, 3 biomarkers related to lactate metabolism were obtained, including COQ2, COQ4, and NDUFV1. And these three biomarkers were enriched in pathways 'antigen processing and presentation' and 'NOD-like receptor signaling pathway'. We found that Macrophages M0 and T cells regulatory (Tregs) were associated with these three biomarkers as well. Overall, the results indicated that lactate-related biomarkers COQ2, COQ4, and NDUFV1 were associated with LN, which laid a theoretical foundation for the diagnosis and treatment of LN.

GC/MS and LC/MS serum metabolomic analysis of Chinese LN patients

China, being a densely populated nation, faces a substantial economic burden due to a high incidence of lupus nephritis (LN) cases. The concealed onset of LN has resulted in many individuals have missed the optimal timing for treatment. The aim of the research is to study the serum metabolomics of Chinese LN patients using gas chromatography (GC)/mass spectrometry (MS) and liquid chromatography (LC)/MS to identify potential diagnostic markers. Fifty LN patients and fifty normal controls, matched for Body Mass Index (BMI) and age, were selected. Serum analysis was conducted using GC/MS and LC/MS, followed by multivariate statistical analysis. Various multidimensional analyses, including principal component analysis, partial least squares discrimination analysis, and orthogonal partial least squares discrimination analysis, along with one-dimensional analyses such as t-tests, were performed. Metabolites with variable importance in projection value > 1 and a p-value < 0.05 were considered critical biomarkers for LN. Furthermore, identified biomarkers delineated relevant metabolic pathways, and a metabolic pathway map was obtained from the database. Forty-one metabolites were identified as potential LN biomarkers, primarily associated with immune regulation, energy metabolism, intestinal microbial metabolism, renal damage, and oxidative stress. The potential for diagnosing LN and other diseases through metabolomics is demonstrated. Future research should explore larger sample sizes, metabolomic comparisons across different diseases and health states, and integration of metabolomics with clinical diagnostics. Such studies will enhance the understanding of metabolomics in medical diagnosis and provide robust support for its practical application.

Identification of pattern recognition receptor genes in peripheral blood mononuclear cells and monocytes as biomarkers for the diagnosis of lupus nephritis

BackgroundThe study aimed to investigate the diagnostic value of lupus-related pattern recognition receptors (PRRs) genes in peripheral blood mononuclear cells (PBMCs) and monocytes (MONs) for lupus nephritis (LN). MethodsPBMCs were isolated from a cohort with 37 LN patients and 39 healthy controls (HCs), and MONs were derived from another cohort with 70 LN patients and 66 HCs. Q-PCR was used to measure the mRNA levels of CGAS, IFNB1, AIM2, IL1Β, NLRC4, NLRP3, NLRP12 and ZBP1 in the PBMCs and MONs. The Mann-Whitney U test was used to compare the data in LN patients and HCs. Eleven GEO datasets of SLE/LN were used to perform differentially expressed genes (DEGs) analysis to these PRR genes. Receiver operating characteristic (ROC) curve analysis was employed to assess the performance of individual genes or the disease prediction model established by combining multiple genes in LN diagnosis. Spearman correlation method was done to analyze the correlation between these PRRs and other clinical characteristics. ResultsThe mRNA levels of five genes (AIM2, NLRC4, IL1B, NLRP12 and ZBP1) in PBMCs, and seven genes (CGAS, IFNB1, AIM2, IL1B, NLRP3, NLRP12 and ZBP1) in MONs of LN patients were significantly higher than those of HCs (P < 0.05). DEGs analysis based on the GEO datasets showed that ZBP1, AIM2 and IL1B were significantly increased in several datasets. The ROC curve analysis indicated that the area under curve (AUC) of the LN prediction models derived from PBMCs or MONs were 0.82 or 0.91 respectively. In addition, the expression levels of these PRRs were correlated with other clinical features in LN patients, including Anti-Sm, ESR, serum Cr, and C3. ConclusionOur study suggests that these lupus-related PRRs might be served as potential biomarkers of LN.

Lupus Nephritis Biomarkers: A Critical Review.

Lupus nephritis (LN), a major complication in individuals diagnosed with systemic lupus erythematosus, substantially increases morbidity and mortality. Despite marked improvements in the survival of patients with severe LN over the past 50 years, complete clinical remission after immunosuppressive therapy is achieved in only half of the patients. Therefore, timely detection of LN is vital for initiating prompt therapeutic interventions and improving patient outcomes. Biomarkers have emerged as valuable tools for LN detection and monitoring; however, the complex role of these biomarkers in LN pathogenesis remains unclear. Renal biopsy remains the gold standard for the identification of the histological phenotypes of LN and guides disease management. However, the molecular pathophysiology of specific renal lesions remains poorly understood. In this review, we provide a critical, up-to-date overview of the latest developments in the field of LN biomarkers.

Proximity extension assay proteomics and renal single cell transcriptomics uncover novel urinary biomarkers for active lupus nephritis

ObjectiveTo identify urinary biomarkers that can distinguish active renal involvement in Lupus Nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE). MethodsUrine from 117 subjects, comprised of inactive SLE, active non-renal lupus, active LN, and healthy controls, were subjected to Proximity Extension Assay (PEA) based comprehensive proteomics followed by ELISA validation in an independent, ethnically diverse cohort. Proteomic data is also cross-referenced to renal transcriptomic data to elucidate cellular origins of biomarkers. ResultsSystems biology analyses revealed progressive activation of cytokine signaling, chemokine activity and coagulation pathways, with worsening renal disease. In addition to validating 30 previously reported biomarkers, this study uncovers several novel candidates. Following ELISA validation in an independent cohort of different ethnicity, the six most discriminatory biomarkers for active LN were urinary ICAM-2, FABP4, FASLG, IGFBP-2, SELE and TNFSF13B/BAFF, with ROC AUC ≥80%, with most correlating strongly with clinical disease activity. Transcriptomic analyses of LN kidneys mapped the likely origin of these proteins to intra-renal myeloid cells (CXCL16, IL-1RT2, TNFSF13B/BAFF), T/NK cells (FASLG), leukocytes (ICAM2) and endothelial cells (SELE). ConclusionIn addition to confirming the diagnostic potential of urine ALCAM, CD163, MCP1, SELL, ICAM1, VCAM1, NGAL and TWEAK for active LN, this study adds urine ICAM-2, FABP4, FASLG, IGFBP-2, SELE, and TNFSF13B/BAFF as additional markers that warrant systematic validation in larger cross-sectional and longitudinal cohorts.

Circulating exosomal microRNAs as biomarkers of lupus nephritis.

Disruption in the delicate symphony of genes, microRNA (miRNA), or protein expression can result in the dysregulation of the immune system, leading to the devastating consequences such as lupus nephritis (LN). The capacity of exosomes to transport miRNAs between cells and modify the phenotype of recipient cells implies their involvement in persistent kidney inflammation. This study unveils identifying two previously undiscovered exosomal miRNAs in the serum of LN patients, offering potential solutions to the current challenges in LN diagnosis and management. Initially, we used a reagent-based kit to isolate serum exosomes from patients with Systemic lupus erythematosus (SLE) and used Trizol method for total RNA extraction. Subsequently, we employed small RNA sequencing to screen for differential expression profiles of exosomal small RNAs. The RT-qPCR method was used to individually validate samples in both the screening and validation cohorts, enabling the identification of candidate small RNAs; specific to LN. We assessed the diagnostic potency using receiver operating characteristic (ROC) curve, and explored the biological roles of miRNAs using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Compared to SLE patients without LN, SLE patients accompanied by LN exhibited significantly spiked levels of exosomal hsa-miR-4796-5p and hsa-miR-7974. The duo of miRNAs, hsa-miR-4796-5p and hsa-miR-7974, exhibited promising potential as biomarkers for diagnosing LN, with an AUC exceeding 0.8. Correlation analysis revealed a strong positive association between these miRNAs and proteinuria, as well as the SLE Disease Activity Index (SLEDAI) score. Moreover, the levels of two miRNAs in LN patients were significantly elevated in comparison to other autoimmune nephritis conditions, such as immunoglobulin A nephropathy (IgAN) and diabetic nephropathy (DN). Furthermore, the bioinformatics analysis indicated that this miRNAs duo can play a pivotal role in the regulation of immune processes by modulating signal pathways, such as the mTOR and PI3K-Akt signaling pathway. This study provides a new ground that serum exosomal miRNAs can effectively identify and predict LN in SLE patients.

Metabolic Markers and Association of Biological Sex in Lupus Nephritis.

Lupus nephritis (LN) is a serious complication for many patients who develop systemic lupus erythematosus, which primarily afflicts women. Our studies to identify biomarkers and the pathogenic mechanisms underlying LN will provide a better understanding of disease progression and sex bias, and lead to identification of additional potential therapeutic targets. The glycosphingolipid lactosylceramide (LacCer) and N-linked glycosylated proteins (N-glycans) were measured in urine and serum collected from LN and healthy control (HC) subjects (10 females and 10 males in each group). The sera from the LN and HC subjects were used to stimulate cytokine secretion and intracellular Ca2+ flux in female- and male-derived primary human renal mesangial cells (hRMCs). Significant differences were observed in the urine of LN patients compared to HCs. All major LacCers species were significantly elevated and differences between LN and HC were more pronounced in males. 72 individual N-glycans were altered in LN compared to HC and three N-glycans were significantly different between the sexes. In hRMCs, Ca2+ flux, but not cytokine secretion, was higher in response to LN sera compared to HC sera. Ca2+ flux, cytokine secretion, and glycosphingolipid levels were significantly higher in female-derived compared to male-derived hRMCs. Relative abundance of some LacCers and hexosylceramides were higher in female-derived compared to male-derived hRMCs. Urine LacCers and N-glycome could serve as definitive LN biomarkers and likely reflect renal disease activity. Despite higher sensitivity of female hRMCs, males may experience greater increases in LacCers, which may underscore worse disease in males. Elevated glycosphingolipid metabolism may poise renal cells to be more sensitive to external stimuli.

Endothelial cell activation and glycocalyx shedding - potential as biomarkers in patients with lupus nephritis.

Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus and an important cause of acute and chronic kidney injury. Early diagnosis of LN and preventing relapses are key to preserving renal reserve. However, due to the complexity and heterogeneity of the disease, clinical management remains challenging. Kidney biopsy remains the gold standard for confirming the diagnosis of LN and subsequent assessment of kidney histopathology, but it is invasive and cannot be repeated frequently. Current clinical indicators of kidney function such as proteinuria and serum creatinine level are non-specific and do not accurately reflect histopathological changes, while anti-dsDNA antibody and C3 levels reflect immunological status but not kidney injury. Identification of novel and specific biomarkers for LN is prerequisite to improve management. Renal function deterioration is associated with changes in the endothelial glycocalyx, a delicate gel-like layer located at the interface between the endothelium and bloodstream. Inflammation induces endothelial cell activation and shedding of glycocalyx constituents into the circulation. This review discusses the potential role of soluble glycocalyx components as biomarkers of active LN, especially in patients in whom conventional serological and biochemical markers do not appear helpful.

Microvascular C5b-9 deposition in non-lesional skin in patients with SLE and its correlation with active lupus nephritis: a prospective observational study

ObjectiveTissue damage in lupus nephritis (LN) is mediated by activation of the classical complement pathway. Complement-mediated upregulation of endothelial cell adhesion molecules is seen in dermal blood vessels of non-lesional...

Urine SERPINC1/ORM1 as biomarkers for early detection of lupus nephritis in MRL-lpr mice.

To evaluate the usefulness of urine SERPINC1 and ORM1 as biomarkers for early detection of lupus nephritis (LN). Using proteomics, we screened for potential urine biomarkers that differentiate LN from systemic lupus erythematosus (SLE) patients without nephritis. In addition, urine levels of target biomarkers were measured by ELISA in 13- and 23-week-old MRL-lpr (murine model for LN) and MRL/MpJ mice. Histological analysis was also performed on the kidneys of 23-week-old mice. Urine SERPINC1 and ORM1 were elevated in SLE patients with newly diagnosed LN compared with SLE patients without LN (SERPINC1, AUC=.892, P<.001; ORM1, AUC=.886, P<.001). Levels of urine SERPINC1 and ORM1 were also significantly higher in MRL-lpr mice than in MRL/MpJ mice at 13 and 23 weeks (SERPINC1: p<.01 and p<.001 at 13 and 23 weeks, respectively; ORM1: p<.01 at 13 and 23 weeks). In contrast, a significant difference in urine albumin between the two groups was only observed at 23 weeks (p<.001) not at 13 weeks (p=.83). Regarding the kidney pathology of MPL-lpr mice, urine ORM1 and urine albumin, but not urine SERPINC1, were positively correlated with the activity index (ORM1, rho =.879, p<.001; albumin, rho =.807, p=.003) and chronicity index (ORM1, rho =.947, p<.001; albumin, rho =.869, p<.001). We propose that urine SERPINC1 and ORM1 are novel biomarkers for early LN.

Urine L-selectin reflects clinical and histological renal disease activity and treatment response in lupus nephritis across multi-ethnicity.

There is an urgent need for novel biomarkers in lupus nephritis (LN). We report a non-invasive urinary biomarker, L-selectin, in two independent multi-ethnic cohorts. uL-selectin was tested cross-sectionally in a Chinese cohort (n=255) and a US cohort (n=219) of SLE patients and controls using ELISA. A longitudinal cohort includes 20 active Chinese LN patients. uL-selectin was significantly increased in active LN patients compared to active non-renal SLE, inactive LN, inactive non-renal SLE, chronic kidney disease patients, and healthy controls. uL-selectin positively correlated with global and renal disease activities as well as histological activity index and chronicity index (CI). Low uL-selectin was an independent predictor for high CI. During follow-up, uL-selectin levels decreased significantly in the complete renal remission group. uL-selectin is a novel biomarker of disease activity and renal histopathology in LN across multiple ethnicities. It also reflects treatment response in LN patients during follow up.

Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) as markers of active lupus nephritis

Background and objectivesDespite much research about lupus nephritis, none of the urinary biomarkers has been proven to be truly reflecting lupus nephritis activity, response to treatment, or prognosis. We aimed to study urinary biomarkers in lupus nephritis and test their relation to kidney damage.Patients and methodsForty patients with systemic lupus erythematosus (SLE) were divided into two graoups: (1) lupus nephritis group with biopsy-proven proliferative lupus nephritis (classes III and IV) and who did not receive immunosuppressive drugs within the preceding 3 months except for glucocorticoids and (2) lupus non-nephritis group with SLE patients without any renal manifestation. We assessed disease activity by the SLE disease activity index. uNGAL, uKim-1, uNGAL to urinary creatinine excretion (mg/dl), and uKim-1 to urinary creatinine excretion were measured in random spot urine samples at the time of renal biopsy and 6 months after the induction therapy.ResultsThe LN group before treatment showed higher levels of uNGAL and uKIM-1 (P-value < 0.001). ROC analysis showed that uNGAL at level of > 59 has a 95 % sensitivity, a 100 % specificity, and an AUC = 0.996 in the ability to diagnose LN. While the uKIM-1 ROC showed that at level of > 1.6, it has an 85 % sensitivity, an 80 % specificity, and an AUC = 0.919. uNGAL and uKIM levels were significantly lower after treatment (P-value < 0.001). No significant correlations were found between urinary markers before and after treatment with other clinical, inflammatory, and serological markers of lupus nephritis.ConclusionuNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio can be used as a predictor and a marker of disease activity for lupus nephritis.Key Points• Renal biopsy is the current standard for diagnosis of lupus nephritis and none of the urinary biomarkers has been fully concluded to have a diagnostic power to reflect the activity or the response to treatment.• However, based on the finding of the current study, uNGAL, uKIM, uNGAL/Creat ratio, and uKIM/Creat ratio showed significant diagnostic performance and were powerful indices of renal involvement in systemic lupus patients and as markers of disease activity.

Urinary Long Non-Coding RNA Levels as Biomarkers of Lupus Nephritis.

Emerging evidence suggests that long non-coding RNA (lncRNA) plays important roles in the regulation of gene expression. We determine the role of using urinary lncRNA as a non-invasive biomarker for lupus nephritis. We studied three cohorts of lupus nephritis patients (31, 78, and 12 patients, respectively) and controls (6, 7, and 24 subjects, respectively). The urinary sediment levels of specific lncRNA targets were studied using real-time quantitative polymerase chain reactions. The severity of proteinuria inversely correlated with urinary maternally expressed gene 3 (MEG3) (r = -0.423, p = 0.018) and ANRIL levels (r = -0.483, p = 0.008). Urinary MEG3 level also inversely correlated with the SLEDAI score (r = -0.383, p = 0.034). Urinary cancer susceptibility candidate 2 (CASC2) levels were significantly different between histological classes of nephritis (p = 0.026) and patients with pure class V nephritis probably had the highest levels, while urinary metastasis-associated lung carcinoma transcript 1 (MALAT1) level significantly correlated with the histological activity index (r = -0.321, p = 0.004). Urinary taurine-upregulated gene 1 (TUG1) level was significantly lower in pure class V lupus nephritis than primary membranous nephropathy (p = 0.003) and minimal change nephropathy (p = 0.04), and urinary TUG1 level correlated with eGFR in class V lupus nephritis (r = 0.706, p = 0.01). We identified certain urinary lncRNA targets that may help the identification of lupus nephritis and predict the histological class of nephritis. Our findings indicate that urinary lncRNA levels may be developed as biomarkers for lupus nephritis.

V-Set Immunoglobulin Domain-Containing Protein 4 as a Novel Serum Biomarker of Lupus Nephritis and Renal Pathology Activity.

To discover novel serum biomarkers that have diagnostic or predictive value in lupus nephritis (LN). Using a quantitative protein microarray, we screened for high-abundant proteome expression in the serum of patients with LN compared to healthy controls. Top candidates from this screening were validated using a larger cohort of patients with LN compared to a disease control cohort (subjects with other chronic kidney diseases) and a healthy control cohort. Promising markers were then selected using a machine-learning model and further validated with a larger patient cohort. The corresponding autoantibodies and immune complexes containing these proteins were also examined. In total, 13 proteins were found to be significantly elevated in LN patient serum in the screening, among which 8 proteins were validated by enzyme-linked immunosorbent assay using 81 serum samples from LN patients and control subjects. Three serum markers with LN diagnostic potential were identified using feature importance analysis and further validated using 155 serum samples from LN patients and control subjects. V-set immunoglobulin domain-containing protein 4 (VSIG4) appeared to be the most promising marker in distinguishing LN from healthy controls, with an area under the curve of 0.93. VSIG4 could also discriminate active LN from inactive LN. Furthermore, serum VSIG4 levels were positively correlated with all of the following clinical parameters: the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score (Spearman's rank correlation rs = 0.42, P < 0.001), the renal domain score of the SLEDAI (rs = 0.46, P < 0.001), the urinary protein-to-creatinine ratio (rs = 0.56, P < 0.001), and the serum creatinine level (rs = 0.41, P < 0.001). Importantly, we found that serum VSIG4 levels tracked with LN disease activity longitudinally, and that serum VSIG4 levels reflected the renal pathology activity index (AI), particularly the AI components of crescent formation and hyaline deposits. VSIG4 may be a promising novel serum biomarker and therapeutic target in patients with LN.