To Örebro University

Background and Aims: Systemic lupus erythematosus (SLE) is characterized by a complex and variable disease course, necessitating continuous clinical and laboratory assessments to monitor organ involvement and disease progression. Lupus nephritis (LN), thmost common organ-threatening manifestation of SLE, is commonly monitored using kidney biopsies, alongside blood and urine parameters. While kidney biopsy remains the gold standard for diagnosis, it is an invasive procedure and provides only a snapshot in time. Therefore, there is growing interest in non-invasive biomarkers that could improve clinical management of LN, aiding in diagnosis, prognostic assessment, and treatment decisions. By critically assessing the quality of existing studies on potential biomarkers—urinary, serum-based, or others—correlating with histological findings, we here explore the challenges in implementing these biomarkers in clinical practice and identify promising candidates for future validation.

Method: A systematic literature search on LN biomarkers was conducted, extending a previous review by Palazzo et al. [1]. Studies in English, published between 2012 and 2024, and involving adult patients with biopsy-proven LN were included. The search focused on studies demonstrating significant correlations between biomarkers and histological findings, particularly the National Institutes of Health (NIH) activity index (AI) and chronicity index (CI), the International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classes, and specific active or chronic lesions. From this search, 96 articles were selected, investigating the potential utility of over 100 biomarkers, which were categorized into groups. The quality of each article was assessed by a multidisciplinary panel of experts utilizing the scoring system by Guyatt et al. [2].

Results: The 96 publications were stratified into various biomarker categories: autoantibodies (n = 6), complement factors (n = 4), cytokines, chemokines, growth factors (n = 26), cell adhesion and surface molecules (n = 8), immune cells (n = 8), markers of kidney damage (n ≈ 20), micro-RNA (n ≈ 10), others (n ≈ 30). The biomarkers were tested against various lesions, both individual and combined, as well as measurements such as NIH AI and CI, and ISN/RPS classes. In quality assessment, over 50% of the articles were weak, 17% were very weak (score <5), and only 1 was deemed robust (score >8). Considering the scores of the respective articles, transforming growth factor beta 1 (TGF-β1) emerged as the biomarker deriving from the most robust study, followed by pentraxin 3 (PTX3), CD163, CD11b, hemopexin, and interleukin 16 (IL-16) (Figure 1).

Conclusion: Our findings highlight the challenges in translating biomarker research into clinical practice for LN. Methodological heterogeneity across studies is a limitation to the interpretation of results. Furthermore, by focusing on selected markers, many studies oversimplify the intricate landscape of histological findings in a kidney biopsy. All clinical trials in LN should store samples for biomarker assessment and validation, prioritizing their ability to accurately reflect specific histological features, evolve with biopsy parameters over time, and demonstrate predictive value for long-term outcomes. Until substantial progress is made in the development of new biomarkers for LN, their clinical applicability will remain limited