Mapping the kidneys: How spatial transcriptomics is changing our understanding of childhood lupus nephritis

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Childhood-onset lupus nephritis (cLN) is a serious kidney disease that affects children with systemic lupuserythematosus (SLE). Researchers have been using advanced technology to understand the disease better, especially how the cells in the kidney are affected. This research is important because many children with cLN do not fully recover with current treatments, leading to long-term kidney damage.

What is cLN?
cLN is a type of kidney disease that develops in children who have SLE.
It can cause long-term kidney damage if not treated effectively.
Current treatments often fail to achieve full recovery, highlighting the need for better therapies.

How the study was conducted: Researchers used a new technology called spatial transcriptomics to study kidney tissue from children with cLN. This method allowed them to look at the cells in the kidney and see which genes they were expressing, all while maintaining the spatial arrangement of the cells. This is different from older methods that required breaking up the tissue, losing important spatial information. The study looked at kidney biopsies from eight children with cLN and four healthy children as controls. The researchers examined over 500,000 cells and identified 30 different types of kidney and immune cells. They used a special tool called InSituType to help identify the cells.

Key findings

  • Immune cells in cLN: The study found that there were more immune cells in the kidneys of children with cLN compared to healthy kidneys. The main immune cells found were macrophages, but there were also more T cells, B cells and plasma cells.
  • Location matters: The location of immune cells within the kidney was found to be significant. For example, macrophages were found in inflamed areas of the kidney called glomeruli, while B cells tended to gather in immune "hotspots" in other parts of the kidney.
  • Macrophage differences: The macrophages inside the glomeruli showed different gene activity compared to those outside. Those within the glomeruli expressed genes related to inflammation and tissue damage, while those outside had more features of tissue-resident macrophages.
  • B cells in cLN: B cells were found to gather in specific areas of the kidney forming immune hotspots. These B cells showed different stages of development suggesting that plasma cells are being produced in these locations.
  • Treatment resistance: A patient with treatment-resistant cLN was studied using serial biopsies, showing that although B cells were depleted in the blood with rituximab treatment, B cells persisted within the kidney, suggesting a cause for treatment failure.
  • Changes in kidney cells: The study found changes in the gene expression of the resident kidney cells (glomerular endothelial, mesangial and podocyte cells) in cLN. The cells were expressing genes related to inflammation and cell-matrix interactions.
  • Heterogeneity: The researchers discovered that even within a single kidney, some glomeruli (the filtering units of the kidney) appeared normal while others showed signs of damage.
  • Gene modules: The study identified groups of genes that are spatially correlated with specific functions. One module was related to inflammation and another to the development of fibrosis (scarring).

Implications of the study
  • The findings highlight the complexity of cLN, showing that it is not just about the presence of immune cells, but also their location and function within the kidney.
  • The study provides a deeper understanding of the changes in the kidney cells in cLN and might guide the development of more precise treatments.
  • The results suggest that treatments should target specific cells and locations to be more effective.
  • The research also shows that current therapies, like rituximab, may not work well because they do not fully clear B cells from the kidney.
  • The data suggest that fibrosis may develop early in cLN and support the use of antifibrotic therapies, in addition to immunosuppressants.
  • The study provides a valuable resource for other researchers studying lupus and kidney disease.

In conclusion, this research provides a detailed look into the cellular and molecular changes that occur in cLN. By using spatial transcriptomics, the researchers were able to uncover new details about how immune cells and kidney cells interact in this disease. These findings could lead to the development of more targeted and effective treatments for children with cLN in the future.
 
Additional information: Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells. Science Translational Medicine. DOI: 10.1126/scitranslmed.adl1666

Location: Oxford, UK

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