B Cell Activating Factor (BAFF) and A Proliferation Inducing Ligand (APRIL) Kidney Biopsy Transcriptomic Signatures Define Subgroups Across Primary Glomerular Diseases

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Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of kidney failure in young adults. Emerging therapeutic strategies may be applied to other renal diseases based on shared immune and non-immune molecular mechanisms. The aim was to explore the potential of BAFF and APRIL transcriptional signatures toward precision medicine approaches in rare glomerular diseases. Methods: Unsupervised analysis of kidney tubulointerstitial RNAseq transcriptomic profiles from living donor controls and patients of different etiologies enrolled in the ERCB (n=37) and NEPTUNE (n= 372) cohorts were analyzed. Immune cell proportion using CIBERSORTx and literature-derived BAFF and APRIL signatures were evaluated. Results: Two distinct molecular subgroups of IgAN patients were identified, with subgroup 2 (45% of the Neptune cohort) exhibiting greater immune and inflammatory activation and more severe clinical characteristics: lower eGFR, higher proteinuria, higher interstitial fibrosis and tubular atrophy at biopsy, higher risk of kidney failure and higher BAFF/APRIL signature score (p<0.01 for all comparisons) compared to group 1. BAFF/APRIL mRNA expression signatures (87% and 78% respectively) were also increased in MCD, MN, DN and FSGS compared to living donor controls and were associated with higher proportion of B-cells/plasma cells. Conclusion: Transcriptomic profiling reveals distinct molecular subtypes of IgAN associated with clinical severity and disease progression. Elevated BAFF and APRIL signaling were also found in other glomerular diseases. This study highlights the potential beneficial effect of targeted therapies for B-cell mediated glomerular diseases. Funding: Commercial Support - Vera Therapeutics

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