The Immune Microenvironment of Transplant Glomerulitis

Nathan A Bracey; Jonathan S Maltzman; Adrienne H Long; Renu Dhanasekaran; Vishnu Shankar; Azam Mohsin; Neeraja Kambham; Gerlinde Wernig; Andrew J Gentles; Mark M Davis; Vivek Charu

doi:10.1016/j.ekir.2025.06.015

The Immune Microenvironment of Transplant Glomerulitis

Kidney Int Rep. 2025 Jun 18;10(9):3113-3127. doi: 10.1016/j.ekir.2025.06.015. eCollection 2025 Sep.

Authors

Nathan A Bracey¹, Jonathan S Maltzman^{2

3}, Adrienne H Long^{1

4}, Renu Dhanasekaran⁵, Vishnu Shankar¹, Azam Mohsin¹, Neeraja Kambham⁶, Gerlinde Wernig⁶, Andrew J Gentles^{6

7}, Mark M Davis^{1

8

9}, Vivek Charu^{6

10}

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, California, USA.
² Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
³ Geriatric Research and Education Clinical Center, Veterans Administration Palo Alto Health Care System, Palo Alto, California, USA.
⁴ Division of Hematology, Oncology, Stem Cell Transplantation, and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA.
⁵ Division of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
⁷ Department of Biomedical Data Science, Stanford University, Stanford, California, USA.
⁸ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA.
⁹ The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
¹⁰ Quantitative Sciences Unit, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

Abstract

Introduction: Transplant glomerulitis is a morphological lesion seen in kidney allograft rejection that is associated with poor outcomes; however, little is known about how immune cells infiltrate and organize specifically within glomeruli.

Methods: We used Co-Detection by Indexing (CODEX) multifluorescent imaging to measure 52 protein markers in a retrospective cohort of 41 human allograft nephrectomies (ANs) and evaluated the immunological landscape of transplant glomerulitis.

Results: Characterization of 18 cell types identified diverse immune cells within inflamed glomeruli, with unique phenotypes and compositions compared with the extraglomerular microenvironment. Immunological phenotypes were conserved across glomeruli within individuals and associated with the general state of injury, with M1 macrophages and effector CD8 T cells associated with mild inflammation. Distance-based spatial analysis further revealed a profibrotic community composed of M2 macrophages, memory CD8 T cells and exhausted CD8 T cells surrounding endothelial cell hubs. These interaction networks were associated with regions of adverse glomerular remodeling, expression of profibrotic proteins, and were more prevalent in individuals with C4d-positive rejection.

Conclusion: These results implicate distinct cell-cell interactions as hallmarks of alloimmune injury and chronic remodeling during transplant glomerulitis and may give rise to new tools for histological risk assessment of clinical rejection syndromes.

Keywords: cell-cell communication; kidney rejection; single-cell; transplant glomerulitis.