Lupus nephritis (LN) is a common complication of systemic lupus erythematosus that presents a high risk of end-stage renal disease. Clinically, the kidney biopsy is used to guide initial therapy in patients with LN but still unsatisfactory. Thus, non-invasive tools stratifying LC patients are urgently needed. Here, we collected 112 urine samples from LN patients and performed in-depth urine proteomics test. Unsupervised clustering distinguished four molecular subtypes (S1-4). S1 was associated with higher acute index (AI) and increased leukocyte infiltration, and showed a high response rate (83%) to prednisolone combined with Mycophenolate mofetil. In S2, keratins were significantly upregulated, indicating their role in cell structure maintaining. S3 displayed the activation of complement system and elevated chronic index. Importantly, Complement C5 was detected in 92% of S3 cases and exhibited higher expression compared with the other subtypes, suggesting the potential therapeutic utility of C5 inhibitors. S4 was characterized by metabolic abnormalities and lower treatment response rate (55%). The overexpression of SLC5A1 emerged as a distinctive hallmark for S4, its inhibitors might prove effective within this context. Further, we also established a logistic regression model that can distinguished LN patients with higher AI index (AUC = 0.935) using three urinary biomarkers (A2M, CORO1A and ART3), which was replicated in an independent validation set. In summary, noninvasive urinary proteomics provides valuable insight into the molecular characteristics for LN and reliable predictors for AI.

Keywords:

Urine proteome, Molecular subtypes, Biomarker, Logistic regression model

References

Yu, Chen et al. Lupus nephritis: new progress in diagnosis and treatment.Journal of autoimmunity vol. 132 (2022): 102871.Fan, Guanjie et al. Urine proteomics identifies biomarkers for diabetic kidney disease at different stages. Clinical proteomics vol. 18,1 32. 29 Dec. 2021.