Kidney Week

Abstract: FR-PO1006

Arteriolar Molecular Pathways in Children after Kidney Transplantation with Preceding Peritoneal Dialysis

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

• Bartosova, Maria, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Maria Bartosova, PhD

• Zhang, Conghui, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Conghui Zhang, PhD

• Messerschmidt, Gesine, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Gesine Messerschmidt

• Marinovic, Iva, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Iva Marinovic, MSc

• Herzog, Rebecca, Medizinische Universitat Wien, Wien, Wien, Austria

Rebecca Herzog, PhD

• Schaefer, Betti, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Betti Schaefer

• Zaloszyc, Ariane, University Hospital Strasbourg, Strasbourg, France

Ariane Zaloszyc, MD, PhD

• Oh, Jun, University Hospital Hamburg, Hamburg, Germany

Jun Oh, MD

• Kratochwill, Klaus, Medizinische Universitat Wien, Wien, Wien, Austria

Klaus Kratochwill, PhD

• Schmitt, Claus Peter, UniversitatsKlinikum Heidelberg, Heidelberg, Baden-Württemberg, Germany

Claus Peter Schmitt, MD, PhD

Group or Team Name

• International Pediatric Peritoneal Biobank.

Background

Patients on peritoneal dialysis (PD) suffer from accelerated vascular disease. Following kidney transplantation (KTx) vascular disease progresses, underlying molecular pathomechanisms are uncertain.

Methods

Omental arterioles microdissected from age-matched children (median 6,5y) with chronic kidney disease (CKD5), on PD with neutral pH, low-GDP-PD fluids, and from children 4-5 weeks after successful KTx and preceding PD (n=5-8/group) underwent multi-omics followed by gene set enrichment-, gene ontology and protein interaction analysis. Key pathways were validated in independent cohorts by quantitative immunohistochemistry (n=15/group) and in vitro.

Results

5000 most variable arteriolar transcripts (p-value<0.05,|r| >0.5) were grouped into 23 modules, 8 significantly differed between CKD5, PD and KTx, one was PD-specific, seven were KTx-specific. PD-specific module was associated with muscle cell proliferation, detoxification, complement activation, with thrombospondin as hub gene. In independent cohorts, thrombospondin and terminal complement complex were higher in PD children vs. CKD5/KTx. KTx-specific modules related to fatty acid biosynthesis, negative regulation of RNA metabolism, cell cycle arrest, and apoptosis. Key drivers of fibrotic process in PD (TGF-ß/pSMAD2/3) persisted high after KTx, cell cycle arrest marker p16 and apoptosis marker cCasp3 were higher after KTx vs. PD/CKD5.
Multi-omics demonstrated upregulation of lipid and fatty acid biosynthesis after KTx, with the hub gene fatty acid synthase (FASN). Intima and media FASN were three-fold higher after KTx vs. PD/CKD5, arteriolar triacylglycerols (TAG) two-fold higher in KTx vs. PD/CKD5. Arteriolar lipidomics revealed long chain TAG in all groups, short chain TAG were increased in KTx arterioles. In vitro, methylprednisolone and tacrolimus, but not mycophenolate increased FASN abundance and activity in human arterial endothelial and vascular smooth muscle cells.

Conclusion

Following KTx, PD-induced complement activation is reversed to CKD level, but profibrotic pathway activation persists and cell cycle arrest, apoptosis and fatty acid biosynthesis increase. Methylprednisolone and tacrolimus presumably activate hub gene FASN, and increase vascular short chain triacylglycerol content.

Funding

• Government Support – Non-U.S.