Background/Purpose: Kidney biopsy remains the gold standard for diagnosis and staging of Lupus Nephritis (LN). Although kidney biopsies are commonly performed in the clinical setting, they carry morbidity. Identification of reliable biomarkers in the blood that correlate with pathological changes in the kidney of LN patients may allow LN diagnosis and staging with only a minimally-invasive drawing of blood.. To that end, we performed a comparative transcriptomic and proteomic biomarker analysis of blood samples and kidney biopsies from LN patients compared to samples from healthy controls and non-lupus kidney disorders. We evaluated whether a molecular signature could identify LN patients versus the comparator disease states and if that signature was similar between the kidney and blood.

Methods: Paired-end strand specific RNASeq was used for gene expression profiling of blood and kidney biopsies from healthy subjects (n=12 and 5 respectively), Lupus Nephritis (10,7) and other kidney diseases such as Diabetic Nephropathy (DN) (10,5), Hypertension (HT) (11,4), Minimal Change (MC) (6,3), and Membranous (MB) (4,4) collected under informed consent. For each sample, approximately 100 million reads were sequenced for a total of ~50 million fragments. Serum collected from these subjects was profiled for autoantibody specificities using ProtoArray®.

Results: RNA-Seq analysis from blood samples revealed a signature enriched in IFN-inducible transcripts unique in the LN patients when compared to the blood transcriptomes from healthy controls or patients with DN, HT, MC, or MB. Remarkably, signatures of “kidney damage” pathways were also identifiable in the blood of LN subjects. Increased expression of the “Complement System” pathway was observed in blood across 3 of the 5 diseases tested (LN,DN,HT). RNASeq analysis of kidney biopsies showed a more homogeneous landscape across the different diseases, with a core of 50 common genes related to kidney injury pathways. Most of the LN kidney biopsy samples exhibited an upregulation of IFN signature genes, that also correlated with blood IFN signatures in the same patients. Broad autoantibody analysis of serum samples indicated that LN patients exhibited vast upregulation of autoantibodies versus healthy controls, in stark contrast to the other kidney diseases examined where autoantibodies were found to be down-modulated (DN, MC, MB).

Conclusion: In this study, we performed blood and kidney transcriptomics and broad serum autoantibody profiling comparing LN patients to patients with other kidney diseases. Pathway analysis of differentially expressed transcripts indicated a unique profile in the blood and kidney biopsies of LN patients in comparison with other kidney diseases. We were able to identify an interferon signature in both the blood and kidney biopsies from LN patients, which correlated between the two tissues. We also identified a kidney damage signature in the blood of LN patients. Further validation studies are needed to determine the utility of using whole blood biomarker testing analysis to replace conventional kidney biopsies in subjects with LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/blood-and-kidney-molecular-profiles-distinguish-subjects-with-lupus-nephritis-from-other-kidney-disorders/