Kidney Week

Abstract: FR-PO1003

Epithelial Injury Patterns Induced by Acute T Cell-Mediated Rejection in Kidney Transplants

Session Information

• Transplantation: Basic
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 2101 Transplantation: Basic

Authors

• Jahn, Lorenz, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Lorenz Jahn

• Pfefferkorn, Anna Maria, Department of Surgery, Experimental Surgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Anna Maria Pfefferkorn, MS, MSc

• Leiz, Janna, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Janna Leiz

• Kulow, Vera Anna, Institute for Translational Physiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Vera Anna Kulow

• Lovric, Svjetlana, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Svjetlana Lovric, MD

• Schmitz, Jessica, Institute of Pathology, Nephropathology Unit, Hannover Medical School, Hannover, Germany

Jessica Schmitz

• Braesen, Jan H., Institute of Pathology, Nephropathology Unit, Hannover Medical School, Hannover, Germany

Jan H. Braesen, MD, PhD

• Scheffner, Irina, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Irina Scheffner, MS

• Fähling, Michael, Institute for Translational Physiology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

Michael Fähling, PhD

• Aigner, Felix, Department of Surgery, Krankenhaus der Barmherzigen Brüder, Graz, Austria

Felix Aigner, DrMed, MBA

• Schmidt-Ott, Kai M., Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Kai M. Schmidt-Ott, MD, DrMed

• Gwinner, Wilfried, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Wilfried Gwinner, MD

• Halloran, Philip F., University of Alberta Alberta Transplant Applied Genomics Centre, Edmonton, Alberta, Canada

Philip F. Halloran, MD, PhD

• Ashraf, Muhammad Imtiaz, Department of Surgery, Experimental Surgery, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany

Muhammad Imtiaz Ashraf, PhD

• Hinze, Christian, Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany

Christian Hinze, DrMed, MD

Background

Acute T-cell mediated rejection (TCMR) remains a major challenge after kidney transplantation, posing risks for the long-term outcome of the transplant. Previous research highlighted the importance of TCMR-induced renal epithelial injury for transplant outcome. Yet, the detailed cellular origin of these injury responses and the associated gene expression profiles remain poorly understood.

Methods

To induce acute rejection, we used two different mouse models (C57BL/6 and BALB/c) for allogeneic kidney transplantation and syngeneic controls. We analyzed the molecular changes in renal gene expression during TCMR by using single nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics on the kidneys 7 days post-transplant. Differentially expressed genes between allogeneic and syngeneic kidneys were analyzed and a published gene set predictive of allograft outcomes was investigated per cell type. All results were compared to our snRNA-seq data from three human TCMR kidney biopsies and three stable allografts.

Results

Mouse kidneys from allogeneic transplantation showed all histological hallmarks of TCMR. SnRNA-seq revealed a strong gene expression response, especially in C57BL/6 kidneys transplanted into BALB/c mice, most pronounced in kidney epithelial cells, particularly in the proximal tubules (PT) and thick ascending limbs (TAL), inducing distinct injury-associated cell states. Spatial transcriptomics identified a heterogeneous spatial distribution of these cell states between cortex and medulla. Published genes indicative of allograft outcome were mostly expressed in injured PT and TAL but showed heterogeneous differential expression in the different injured PT and TAL cell states. Cross-species analysis revealed a substantial overlap of epithelial cell states between mouse and human TCMR.

Conclusion

Our study offers a detailed exploration of cell type-specific gene expression changes during TCMR in humans and mice. The analysis of allograft outcome-associated genes revealed their origin from various injured epithelial cell states. This insight may help identify injured cell states most responsible for reduced graft function, potentially enabling targeted therapeutic interventions.