Urinomics as a guide to the renal immune landscape in SLE
General Audience Summary
The most common organ-specific form of lupus is known as lupus nephritis, which means inflammation of the kidneys. Many patients with lupus nephritis must undergo surgical kidney biopsies to monitor their condition. Since these procedures are invasive and not without risk, other methods to monitor kidney function are needed. Urine tests are already done to monitor some aspects of lupus nephritis treatment, and would be an ideal replacement for kidney biopsies. Dr. Mohan’s research has already identified several promising markers in the urine of lupus nephritis patients that seem to be associated with clinically active disease. In this study, Dr. Mohan will be comparing how urine testing for these markers compares to testing kidney biopsies in detecting active lupus nephritis and monitoring treatment response.
What this study means for people with lupus
If urine screening is successful, this less invasive method of patient monitoring may remove the need for kidney biopsies to diagnose and monitor lupus nephritis.
Scientific Abstract
Two single-cell-RNAseq analyses of LN kidneys have been reported. Independent of those studies, two proteomics screens of LN urine (using orthogonal platforms) in our laboratory have uncovered 388 proteins to be elevated in active LN. Overlap of OMICs readouts: Based on both the above OMICs screens executed, we have identified 15 molecules that satisfy the following 3 criteria: (a) The implicated protein is elevated in active LN urine, compared to urine from control SLE patients; (b) The molecule is elevated in LN, within renal-infiltrating immune cells, at the RNA level; and (c) The selected molecule is expressed predominantly within a single immune cell type within LN kidneys (based on the scRNAseq data). Hypothesis: The 15 LN-WBC-Panel urine proteins may serve as surrogates of specific renal immune cell infiltrates in LN, and may hence have biomarker potential in predicting clinical or histological disease severity. Based on the above findings from two related tissues drawn from two independent cohorts, using two orthogonal OMICs platforms, we propose 2 Aims. Aim 1: To ascertain if urine levels of the 15 proteins in LN-WBC-Panel can be used to track specific WBC subsets within LN kidneys, including total macrophages, M1 macrophages, CD16+ phagocytic macrophages, tissue-resident macrophages, M2 macrophages, total T-cells, TFH, NK cells, CTLs, activated B-cells, plasmablasts, and total immune infiltrates, using paired urine/kidney samples. Aim 2: To ascertain if the 15 urine proteins in LN-WBC-Panel (and by inference, renal infiltration of specific immune cells) are predictive of clinically active LN, in a cross-sectional cohort, or predictive of treatment response to induction therapy of LN. Significance: Intra-renal activated B-cells and plasmablasts are implicated in local autoantibody production, tissue pathology and reduced GFR. Intra-renal T-cells, effector T-cells, TFH, CTL and NK cells have been implicated in tissue damage and/or reduced glomerular function in LN. Similar pathogenic roles have been accorded to myeloid cells in LN, M1 macrophages in particular. Being able to track these intra-renal WBC infiltrates as a function of disease course/severity, non-invasively, avoids the need for serial renal biopsies. Innovation: 1?Urine biomarkers that predict specific renal infiltrates have never been reported before. 2?How temporal changes in specific intra-renal WBC subsets (and intra-renal marker proteins) relate to clinical or histological treatment response is also a black box. 3?Little is known about the 15 proteins to be pursued here although several have been implicated in SLE/LN and/or autoimmunity/inflammation.