Diagnostic test accuracy of novel biomarkers for lupus nephritis—An overview of systematic reviews

Abstract

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiorgan inflammatory involvement and a mortality rate that is 2.6-fold higher than individuals of the same age and sex in the general population. Approximately 50% of patients with SLE develop renal impairment (lupus nephritis). Delayed diagnosis of lupus nephritis is associated with a higher risk of progression to end-stage renal disease, the need for replacement therapy, and mortality. The initial clinical manifestations of lupus nephritis are often discrete or absent and are usually detected through complementary tests. Although widely used in clinical practice, their accuracy is limited. A great scientific effort has been exerted towards searching for new, more sensitive, and specific biomarkers in recent years. Some systematic reviews have individually evaluated new serum and urinary biomarkers tested in patients with lupus nephritis. This overview aimed to summarize systematic reviews on the accuracy of novel serum and urinary biomarkers for diagnosing lupus nephritis in patients with SLE, discussing how our results can guide the clinical management of the disease and the direction of research in this area. Methods The research question is “What is the accuracy of the new serum and urinary biomarkers studied for the diagnosis of LN in patients with SLE?”. We searched for systematic reviews of observational studies evaluating the diagnostic accuracy of new serum or urinary biomarkers of lupus nephritis. The following databases were included: PubMed, EMBASE, BIREME/LILACS, Scopus, Web of Science, and Cochrane, including gray literature found via Google Scholar and PROQUEST. Two authors assessed the reviews for inclusion, data extraction, and assessment of the risk of bias (ROBIS tool). Results Ten SRs on the diagnostic accuracy of new serum and urinary BMs in LN were selected. The SRs evaluated 7 distinct BMs: (a) antibodies (anti-Sm, anti-RNP, and anti-C1q), (b) cytokines (TWEAK and MCP-1), (c) a chemokine (IP-10), and (d) an acute phase glycoprotein (NGAL), in a total of 20 review arms (9 that analyzed serum BMs, and 12 that analyzed BMs in urine). The population evaluated in the primary studies was predominantly adults. Two SRs included strictly adults, 5 reviews also included studies in the paediatric population, and 4 did not report the age groups. The results of the evaluation with the ROBIS tool showed that most of the reviews had a low overall risk of bias. Conclusions There are 10 SRs of evidence relating to the diagnostic accuracy of serum and urinary biomarkers for lupus nephritis. Among the BMs evaluated, anti-C1q, urinary MCP-1, TWEAK, and NGAL stood out, highlighting the need for additional research, especially on LN diagnostic panels, and attempting to address methodological issues within diagnostic accuracy research. This would allow for a better understanding of their usefulness and possibly validate their clinical use in the future. Registration This project is registered on the International Prospective Registry of Systematic Reviews (PROSPERO) database (CRD42020196693).

Lupus Nephritis Risk Factors and Biomarkers: An Update

“…All these urinary cell membrane biomarkers can be used to monitor the treatment response and flares [125], and at baseline, the NGAL levels best predict, as compared to VCAM and KIM1, responders from non-responders 6 months after the induction phase with an AUC = 0.78 [37]. ROC and/or Cox regression analysis further showed that persistently high urinary VCAM1, NGAL, KIM1, and sCD163 levels can predict ESKD evolution [37,116,125,126]. The added value to combine these markers needs to be further evaluated.…”

“…The top five urinary cytokines/chemokines evaluated in LN included: tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK); monocyte chemoattractant protein-1 (MCP-1/CCL2); IFN inducible protein-10 (IP-10/CXCL10); B-cell-activating factor of the tumor necrosis factor family (BAFF/BLySS); and proliferation-inducing ligand (APRIL) [114,115]. Among them, biomarkers with a good/very good AUC for predicting LN included urinary MCP-1/CCL2 (AUC = 0.90) > BAFF (AUC = 0.825) = TWEAK (AUC = 0.82) > IP-10 (0.6 < AUC < 1.0) [116,117]. When combined, urinary MCP-1/CCL2 and TWEAK are effective in discriminating between an active and inactive LN (AUC = 0.89), and ESKD evolution (AUC = 0.78).…”

Lupus Nephritis Biomarkers: A Critical Review

“…For instance, B-cell activating factor (BAFF or BLyS), produced by glomerular macrophages and mesangial cells, stimulates B-cell activation both directly and by inducing the production of pro-inflammatory molecules, such as IFN-α, perpetuating a detrimental cycle in the renal microenvironment. Moreover, cytokines, such as urinary monocyte chemoattractant protein-1 (MCP-1/CCL2), BAFF, and TNF-related weak inducer of apoptosis (TWEAK), are pertinent in predicting active LN, assessing therapeutic responses, and forecasting disease flares [53,54].…”

Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review

“…In an overview of systematic reviews by Guimaraes et al, the biomarkers with the best accuracy profile were urinary tumor necrosis factor-like weak inducer of apoptosis (uTWEAK), a member of the TNF superfamily, urinary monocyte chemoattractant protein-1 (uMCP-1), and urinary neutrophil gelatinase-associated lipocalin (uNGAL), which were more sensitive than specific for most of the analyzed outcomes [ 111 ]. SLE patients with active kidney disease have significantly higher urinary TWEAK levels than SLE patients without active kidney disease [ 112 ].…”