Single-cell RNA sequencing of skin and kidney cells in lupus nephritis provides insights into pathogenesis and indicates novel potential biomarkers

Abstract

Abstract Classification and treatment decisions in lupus nephritis (LN) are largely based on renal histology. Single-cell RNAseq (scRNAseq) analysis may accurately differentiate types of renal involvement at the transcriptomic level, and better inform treatment decisions and prognosis. scRNAseq was performed on kidney and non-lesional skin tissue collected from clinically indicated renal biopsies, and skin biopsies obtained at the time of renal biopsies, in 20 systemic lupus erythematosus (SLE) patients. Cell-types were determined using principal component analysis and tSNE plotting, resulting in the definitive identification of keratinocytes, tubular cells, mesangial cells, fibroblasts, endothelial cells, and leukocytes. Tubular cells in patients with proliferative nephritis demonstrated upregulated TNF signaling compared with membranous nephritis. Interestingly, keratinocytes of patients with proliferative nephritis also demonstrated upregulated TNF signaling. Furthermore, tubular cells of patients who did not respond to standard immunosuppressive treatment showed upregulation of extracellular matrix proteins and fibrotic markers at the time of biopsy. Using logistic regression analysis, a 4-gene tubular fibrosis score was created which predicted response to treatment, with an area under curve of 0.9. We conclude that scRNAseq using small amounts of renal biopsy tissue in SLE can differentiate between the different classes of LN, and provide important insights into potential pathogenic mechanisms. Further, changes in the skin of LN patients can provide a useful source of biomarkers and may reflect important information concerning concurrent kidney pathological events.