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Updated: Jul 5, 2025
Analyses of Proteinuria, Renal Infiltration of Leukocytes, and Renal Deposition of Proteins in Lupus-prone MRL/lpr Mice
Published on: June 8, 2022
Immune and molecular landscape behind non-response to Mycophenolate Mofetil and Azathioprine in lupus nephritis
Raúl López-Domínguez1, Juan Antonio Villatoro-García1, Concepción Marañón2
1GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada, Andalusian Regional Government, PTS Granada.
Abstract:
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.
Insights
Discover why lupus nephritis treatments fail. New research reveals distinct molecular mechanisms and blood cell differences in patients not responding to azathioprine or mycophenolate mofetil, paving the way for improved therapies.
Area of Science:
- Immunology
- Nephrology
- Genomics
Background:
- Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus, often leading to kidney failure.
- Current therapies like mycophenolate mofetil (MMF) and azathioprine (AZA) have limited long-term remission rates (40-30%), highlighting a critical knowledge gap in treatment non-response.
Approach:
- Analyzed a longitudinal cohort of LN patients, integrating clinical, cellular, and transcriptomic data.
- Utilized differential gene expression analysis and single-cell RNA sequencing to identify non-response mechanisms.
- Employed mechanistic modeling to propose potential add-on therapies.
Key Points:
- Identified distinct gene-expression signatures associated with non-response to MMF and AZA.
- Revealed that non-response to AZA and MMF involves different cell subsets and regulatory functions.
- Characterized specific blood cell populations mediating treatment failure in LN.
Conclusions:
- Elucidated novel molecular insights into treatment failures in lupus nephritis.
- Findings suggest distinct cellular and molecular pathways underlie non-response to standard LN therapies.
- Provides a foundation for developing targeted add-on treatments to enhance therapeutic efficacy in non-responsive LN patients.
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