Innovative Technology Enhances Cellular and Molecular Insights into Kidney Lesions

Researchers have demonstrated the feasibility of a morphological-based approach to interpreting spatial transcriptomic (ST) data, helping to improve understanding of the lesions that occur in chronic kidney disease (CKD), at both the cellular and molecular levels. A recent study in The American Journal of Pathology, published by Elsevier, details how this new method could lead to the identification of new biomarkers and therapeutic strategies for patients.

ST technologies are a rapidly developing new tool for measuring RNA in their original spatial context, giving a molecular mechanistic dimension to tissue morphology. The application of ST technologies has already yielded important insights across many different tissues and disease models. By combining profiling of gene expression patterns with the spatial information of cells in tissues, ST provides a more complete understanding of the molecular and cellular organization of tissues and lesions.

Lead investigator Benjamin D. Humphreys, MD, PhD, Division of Nephrology, Department of Medicine, and the Department of Developmental Biology, Washington University in St. Louis, explains, "During ST data analysis, computationally-annotated clusters are often superimposed on a histological image. However, tissue morphology by standard light microscopic pathologic evaluation is not considered. This may preclude assimilation of important information that can help interpret the ST data. The kidney is a particularly heterogeneous organ in morphologic terms, with a high degree of spatial and temporal lesion variability often present in pathologic situations. We conducted a histopathological-based analysis of spatial transcriptomics on four human kidney samples with CKD, corresponding as closely as possible to how a kidney biopsy is interpreted in clinical practice."

The study demonstrates how:

• Morphological and ST cross-analysis can help identify lesions within tissues such as tertiary lymphoid organs in the kidney.

• The cellular composition of a specific lesion can be determined, sometimes beyond its morphological appearance, as in the case of the papillary tumor identified.

• The molecular mechanisms of lesion processes can be identified by comparing lesions at different stages, as in the case of glomerular fibrosis or tubular atrophy.

• To identify potential new genes such as CXCL12 or FXYD5 that may be involved in glomerular fibrosis.

• This method combining traditional histopathology with ST data can pave the way for the future of molecular microscopy and precision pathology.

Lead author Pierre Isnard, MD, PhD, Division of Nephrology, Department of Medicine, and the Department of Developmental Biology, Washington University in St. Louis, concludes, "ST technologies are new and increasingly used in the life sciences, but there is a lack of studies showing their benefits and applications. Here, we demonstrate the complementary nature of these technologies to standard morphological analysis of tissue for identifying, classifying, and understanding lesions. The value of these technologies in healthcare remains to be demonstrated. However, these methods provide a better understanding of the cellular and molecular mechanisms of diseases, which may help identify new biomarkers and/or therapeutic strategies for patients. "

Notes for editors

The article is “Histopathologic Analysis of Human Kidney Spatial Transcriptomics Data: Toward Precision Pathology,” by Pierre Isnard, Dian Li, Qiao Xuanyuan, Haojia Wu, and Benjamin D, Humphreys (https://doi.org/10.1016/j.ajpath.2024.06.011). It appears in The American Journal of Pathology, volume 195, issue 1 (January 2025), published by Elsevier.

The article is openly available at https://ajp.amjpathol.org/article/S0002-9440(24)00274-8/fulltext.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected] to request a PDF of the article or more information. To reach the study’s authors contact Benjamin D. Humphreys, MD, PhD, at [email protected], or Pierre Isnard, MD, PhD, at [email protected].

The study was supported by NIH grants UC2DK126024 and U54DK137332, Assistance Publiquee–Hôpitaux de Paris (France), Philippe Foundation (United States), and Institut Servier Foundation (France).

About The American Journal of Pathology

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.org

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