Identifying Genetic and Immunological Determinants of Childhood Lupus Nephritis

Systemic lupus erythematosus (SLE) can cause devastating organ damage, including the kidney, or lupus nephritis. Approximately 20% of SLE cases are diagnosed in childhood, and many patients with childhood-onset SLE develop lupus nephritis, which is difficult to treat and often life-threatening. Patients with Hispanic, African, Native American, and Asian ancestry have a higher frequency of kidney involvement and typically develop more severe symptoms. Therefore, it is crucial to tailor interventions to high-risk groups based on underlying mechanisms, which are likely influenced by ancestry.

The team, led by Dr. Hsieh, will apply innovative technologies to visualize molecular, cellular, and structural changes in over 400 kidney biopsies from pediatric patients across five countries and thirteen institutions to use this information to improve the categorizing of kidney disease, enhance the ability to predict risk for lupus nephritis, and promote precision medicine for treating lupus nephritis patients. They will determine if there is an association between the observed changes in the kidney biopsy samples and clinical outcomes such as clinical disease category/classification and kidney function. In some cases, SLE is caused by an alteration, or mutation, in a gene, and genetic forms of SLE are increased in pediatric cases. The team will identify genetic mutations in patients with childhood-onset lupus nephritis and investigate their correlation with distinct biopsy patterns and clinical outcomes.  Combining tissue-specific information from kidney biopsies with identified changes in the genetic code of children with lupus nephritis, particularly those of racial/ethnic ancestries with the worst disease outcome, will enable personalized treatment plans and enhance care for children affected by this devastating condition.

What this means for people with lupus:

For lupus patients, this study could revolutionize the current diagnosis and treatment approach. The current classification system for kidney biopsies is not sensitive or specific enough to characterize specific changes in the kidney or predict how a patient will respond to treatment.  By identifying drivers of lupus nephritis, the study can shift the diagnosis and treatment strategy, currently based on a limited biopsy examination, to one guided by underlying immune system and genetic characteristics.

Systemic lupus erythematosus (SLE) is a multi-organ rheumatologic disease with heightened renal disease incidence and severity in children. Unfortunately, few children with childhood-onset lupus nephritis (cLN) achieve complete remission using available therapies, resulting in accumulating damage and progression to chronic kidney disease. Patients with Hispanic, African, Native American, and Asian ancestry develop SLE at younger ages and have a higher risk of kidney involvement than individuals of European descent. However, children of these races/ethnicities are under-represented in clinical trials. In addition, conventional clinical and laboratory assessments are not sufficiently sensitive or specific to detect incipient renal disease or predict treatment response, underscoring the need to better delineate the mechanisms that drive cLN. This gap in our understanding of cLN immunopathogenesis constitutes a significant hurdle to the implementation of precision medicine. The objective of this proposal is to determine the precise molecular, cellular, and histopathological features of cLN in a manner that is spatially localized within kidney stromal compartments, and to correlate these with clinical outcomes.

To achieve this goal, we have assembled a large cohort of cLN subjects (~400) encompassing diverse racial/ethnic backgrounds from 13 collaborating institutions across 5 countries. The following analyses will be applied to patients’ kidney biopsy and DNA samples: Project 1) single cell resolution, high-dimensional transcriptomic and protein imaging of cLN kidney biopsy tissue using the CosMX Spatial Molecular Imager and multiplexed ion beam imaging, respectively; Project 2) digital pathology and morphometric scoring of cLN histopathology; and Project 3) whole exome sequencing for rare genetic variants linked with cLN and cSLE development. These data will be integrated with clinical data collected at 0, 6, and 12 months to identify predictors of treatment response.

Our central hypothesis is that in situ single-cell imaging of kidney biopsies will provide insights into underlying pathophysiology that can be linked to histopathological phenotypes, facilitating precision medicine in cLN. We also posit that pathogenic genetic variants will drive tissue-specific histopathologic changes, supporting pathway-specific treatment selection.

Our approach is innovative in that it is the first to apply both state-of-the-art in situ single cell analytical platforms and whole exome sequencing to profile cLN immunopathology, with the goal of identifying candidate pathways for patient-specific immunotherapy. The proposed research is significant because it will: 1) provide new insights into cLN pathogenesis at the tissue level; 2) identify histopathologic features linked with clinical outcomes, allowing improved use of diagnostic kidney biopsies for treatment decisions; 3) uncover candidate immune pathways that might be leveraged as drug targets.