Immune and molecular landscape behind non-response to Mycophenolate Mofetil and Azathioprine in lupus nephritis therapy.
Raul Lopez-DominguezJuan Antonio Villatoro-GarcíaConcepción MarañónDaniel W GoldmanMichelle A PetriPedro Carmona-SaezMarta Eugenia Alarcón-RiquelmeDaniel Toro-DominguezPublished in: Research square (2024)
Lupus nephritis (LN) represents one of the most severe complications of systemic lupus erythematosus, leading to end-stage kidney disease in worst cases. Current first-line therapies for LN, including mycophenolate mofetil (MMF) and azathioprine (AZA), fail to induce long-term remission in 60-70% of the patients, evidencing the urgent need to delve into the molecular knowledge-gap behind the non-response to these therapies. A longitudinal cohort of treated LN patients including clinical, cellular and transcriptomic data, was analyzed. Gene-expression signatures behind non-response to different drugs were revealed by differential expression analysis. Drug-specific non-response mechanisms and cell proportion differences were identified. Blood cell subsets mediating non-response were described using single-cell RNASeq data. We show that AZA and MMF non-response implicates different cells and regulatory functions. Mechanistic models were used to suggest add-on therapies to improve their current performance. Our results provide new insights into the molecular mechanisms associated with treatment failures in LN.
Keyphrases
- single cell
- end stage renal disease
- gene expression
- systemic lupus erythematosus
- newly diagnosed
- ejection fraction
- rna seq
- chronic kidney disease
- healthcare
- prognostic factors
- peritoneal dialysis
- stem cells
- dna methylation
- induced apoptosis
- risk factors
- disease activity
- emergency department
- rheumatoid arthritis
- cell proliferation
- mesenchymal stem cells
- oxidative stress
- genome wide
- signaling pathway
- smoking cessation
- data analysis