Background/Purpose: Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE), associated with significant morbidity and mortality. IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, characterized by IgA deposition in the glomeruli and subsequent renal damage. Although LN and IgAN share some clinical and immunological similarities, their underlying pathogenic pathways are likely distinct, necessitating further research into their molecular profiles. While the transcriptomic profiles of whole blood samples from SLE patients have been investigated in different cohorts and pointed to the dysregulations of key immune pathways, the differences have not been closely examined in the kidney for LN and IgAN. This study evaluated and compared the transcriptomic profiles of whole blood and kidney biopsy samples from the LN and IgAN patients, as well as the matching healthy controls.

Methods: Samples from 52 patients (34 with LN and 18 with IgAN) were included in this study. Whole blood samples (33 LN and 18 IgAN) were collected in PAXGene tubes. Kidney biopsy samples (24 LN and 16 IgAN) were collected following standard clinical practice, with residual samples preserved for transcriptomic analysis. Healthy control samples including whole blood (n=30) and kidney tissue (n=7) were obtained independently. RNA was extracted from whole blood and kidney samples and used for standard RNA sequencing analysis. In this analysis, statistical significance for differentially expressed genes (DEGs) was defined as a fold change > 2 and FDR < 0.05. Interferon (IFN) gene signature enrichment was quantified using gene set variation analysis (GSVA).

Results: In comparison to healthy controls, there were 2151 differentially expressed genes (DEGs) identified in whole blood of LN patients and 200 DEGs in IgAN patients, respectively. The LN vs IgAN comparison revealed 1054 DEGs. LN DEGs were enriched in Reactome pathways related to “innate immune” and “neutrophil activation”, while IgAN DEGs were enriched in “B cell” and “Fc receptor signaling” pathways. Both LN and IgAN kidney samples exhibited over 3000 DEGs compared to controls and shared similar enriched pathways, with IFN pathway further enriched in LN. The kidney IFN gene signature score correlated with serum creatinine levels and eGFR in both diseases.

Conclusion: Transcriptomic analysis highlighted similar and distinct dysregulated pathways in LN and IgAN whole blood and kidney. Greater differences were observed in whole blood transcriptomics, indicating a greater extent of systemic immunological dysregulation between LN and IgAN. Renal IFN pathway activation was prominent in LN and correlated with the severity of kidney dysfunction in both diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptional-profiling-of-whole-blood-and-kidney-biopsy-samples-from-lupus-nephritis-and-iga-nephropathy-patients-suggests-different-disease-pathways/