Defining fibroblast heterogeneity and its association with kidney function loss in lupus nephritis

Lupus nephritis is a serious complication of lupus that causes inflammation and scarring in the kidneys. Despite current treatments, many people with lupus nephritis still lose kidney function over time, which can lead to kidney failure. One of the biggest challenges doctors face is knowing which patients are likely to get worse and how to treat them more precisely. Right now, kidney biopsies are used to understand disease severity, but these are invasive and do not always give a clear picture of how the disease will evolve.

This project aims to solve that problem by studying special cells in the kidney called fibroblasts. These cells are involved in scarring and tissue repair, and recent research suggests that not all fibroblasts are the same. Some may drive harmful scarring, while others may help in healing. Using a powerful new technology called spatial transcriptomics, the research team will map out the different types of fibroblasts in kidney biopsies from people with lupus nephritis. This will allow us to identify which specific types are associated with future kidney damage.

In the second part of the study, the researchers will analyze urine samples from these same patients to find proteins that match the harmful fibroblast types found in the kidney. The goal is to develop a noninvasive urine test—a “liquid biopsy”—that can monitor the presence and activity of these harmful fibroblast cells over time in response to treatment, without needing repeated kidney biopsies.

By combining cutting-edge technology with real patient samples, this research could lead to better tools to predict who is at risk of kidney failure and help doctors personalize treatment early—before irreversible damage occurs. It may also discover new ways to block harmful fibroblasts potentially leading to new treatments. Ultimately, this work has the potential to change how lupus nephritis is diagnosed and managed, improving quality of life and long-term outcomes for people living with lupus.

The ultimate treatment goal in lupus nephritis (LN) is to prevent irreversible damage and thereby avert chronic kidney disease and end-stage kidney disease (ESKD). In preliminary data from the Accelerating Medicines Partnership (AMP), we followed patients for up to 8 years and found that approximately a third experienced sustained estimated glomerular filtration rate (eGFR) loss >40% or progressed to ESKD. Urine proteomics revealed that persistent elevation of myofibroblast activation markers (such as Tenascin C) during the first year after diagnosis strongly predicted future eGFR decline. Importantly, this association was observed both in patients who achieved proteinuric remission (UPCR <0.5 at 1 year) and those who did not, indicating that ongoing fibrogenic activity may be missed by conventional response measures.  Fibroblasts are a heterogeneous cell population with diverse roles in inflammation, tissue remodeling, and fibrosis. While specific fibroblast subsets have been implicated in rheumatoid arthritis pathogenesis and treatment resistance, the heterogeneity and functional roles of intrarenal fibroblasts in LN remain poorly understood.

Our central hypothesis is that specific intrarenal fibroblast subpopulations contribute to progressive kidney functional decline in LN and can be tracked noninvasively using urine proteomics. We propose a two-part study:

Aim 1: Define fibroblast heterogeneity in LN kidneys and identify subsets associated with subsequent eGFR loss. Using Xenium spatial transcriptomics, we will profile 5,101 genes in 30 archival FFPE renal biopsies from AMP LN patients with known long-term outcomes (casecontrol design). We will identify distinct fibroblast subpopulations and assess their spatial context and association with progressive eGFR decline (>40% over time).

Aim 2: Establish a noninvasive urine proteomic signature that reflects fibroblast subtype activity and predicts kidney functional loss. We will expand our preliminary work to more proteins and more patients (Olink+Somascan ~9,000 proteins, 237 patients – 4 time points) to define the longitudinal urinary signatures that predict eGFR loss. We will then integrate intrarenal fibroblast expression profiles from Aim 1 with longitudinal urine proteomic data. This will enable the identification and validation of urine proteins indicative of disease-driving fibroblast activity, with the goal of developing a “liquid biopsy” to longitudinally monitor disease progression and response to treatment.

This proposal aligns with LRA’s priorities in molecular stratification, human-based research, and biomarker discovery. It leverages advanced spatial transcriptomics, longitudinal clinical and proteomic datasets, and interdisciplinary expertise. We expect Aim 1 to define intrarenal fibroblast subtypes—such as inflammatory or profibrotic populations—associated with histologic fibrosis and eGFR decline. Aim 2 will identify urine proteins that reflect disease-driving fibroblast activity (for longitudinal monitoring) and predict kidney function loss, improving upon traditional clinical markers. Together, these results will offer novel insights into the role of fibroblasts in LN by defining their spatial niches, cellular interactions, and transcriptional programs, and identifying potentially targetable mechanistic pathways. This work will lay the foundation for precision monitoring and therapeutic targeting of fibrosis in lupus nephritis.