Membrane Attack Complex (MAC) and Other Complement Components as Markers of Kidney Injury and Treatment Response in Patients with Lupus Nephritis

Lupus nephritis (LN) has significant morbidity and mortality given nonspecific treatment approaches. Only 24 to 50% of patients respond to current B and/or T cell targeting treatments and 10 to 30% of LN patients progress to end-stage renal disease (ESRD) within 10 years. The complement pathway is a promising target for LN treatment because it plays a central role in pathogenesis. LN patients who respond poorly to current therapies likely have complementmediated inflammation as the main cause of kidney damage. There is an urgent need for complement biomarkers to identify these non-responders and guide targeted therapies. The membrane attack complex (MAC) is a viable marker of renal outcome because it causes cell membrane lysis, drives inflammation and is involved in tubulointerstitial injury. The overall goal of this proposal is to evaluate MAC and other complement components as a marker of kidney injury and treatment response. We hypothesize that LN patients with MAC and other complement components in kidney tissues and urine will have severe complement-mediated kidney injury and worse outcomes. Our hypothesis will be tested using three different approaches: immunohistochemistry, urine proteomics and single-cell RNA sequencing (scRNAseq). This K-Bridge award will enable me to generate preliminary data, publications and broaden the scope of this study in response to reviewers' comments. Studies will be conducted using urine proteomics and scRNA-seq data to strengthen the premise of this research and optimize methods for a first K23 resubmission, with the following aims: 1) to associate MAC deposition in paraffin embedded kidney biopsies with renal outcomes; 2) to determine urinary complement profiles among LN patients using mass spectrometry; and 3) to identify complement gene expression in kidney cells using existing scRNA-seq data from the Accelerating Medicine Partnership (AMP) Lupus Network. We expect to find MAC in kidney tissue and urine among LN patients with worse renal outcomes and discover new complement biomarkers using omics analyses. This K-Bridge award will enable me to generate preliminary data, publications and broaden the scope of this study in response to reviewers' comments. Studies will be conducted using urine proteomics and scRNA-seq data to strengthen the premise of this research and optimize methods for a first K23 resubmission, with the following aims: 1) to associate MAC deposition in paraffin embedded kidney biopsies with renal outcomes; 2) to determine urinary complement profiles among LN patients using mass spectrometry; and 3) to identify complement gene expression in kidney cells using existing scRNA-seq data from the Accelerating Medicine Partnership (AMP) Lupus Network. We expect to find MAC in kidney tissue and urine among LN patients with worse renal outcomes and discover new complement biomarkers using omics analyses.