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Kidney Week

Abstract: FR-PO1013

Inflammatory Status in Deceased Kidney Donors Led by Impaired Mitochondrial Metabolism through the HIF1α Hypoxia Pathway

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

  • Guillen-Gomez, Elena, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Vilardell, Jordi, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Arce, Yolanda, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Silva, Irene, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Fernandez-Veledo, Sonia, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Catalunya, Spain
  • Facundo, Carme, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Bardaji de Quixano, Beatriz, Fundacio Puigvert, Barcelona, Catalunya, Spain
  • Diaz Encarnacion, Montserrat M., Fundacio Puigvert, Barcelona, Catalunya, Spain

Group or Team Name

  • Group of Renal Inflammatory Diseases (GERI).
Background

The type of kidney donor determines prognosis of recipient’s renal function, being worst in deceased donors’ (DD) grafts than in living donors’ (LD). This is due to the pre-implantation inflammation status and development of fibrotic processes in DD, related to hypoxia status, where even the cause of death can make a difference.
Mitochondrial succinate dehydrogenase (SDH) complex is associated to inflammatory markers and macrophages. Succinate plays a key role in inflammatory processes. HIF-1α is a transcription factor regulated by succinate and hypoxia, setting a link between cellular energy metabolism, oxygen levels and response to stress situations.
The aim of this study is to determine whether hypoxia processes through HIF-1α can increase renal succinate and induce infiltration of inflammatory cells in DD.

Methods

Expression of 159 genes was analyzed from pre-implantation kidney biopsies of 47 kidney DD and 19 LD to determine effect of hypoxia on kidney inflammation/fibrosis. Genes with strong positive correlation with HIF1α were grouped in functional clusters. Serum succinate levels were measured in 27 brain-death DD (BD-DD) and 10 healthy volunteers (HV) (comparable to LD). Levels of 18 monocyte/macrophage cytokines stimulating pro-inflammatory (M1) or restorative (M2) macrophages were determined in serum of BD-DD and HV, and the expression of characteristic cell markers in circulating monocytes extracts of these subjects.

Results

DD exhibited higher serum succinate levels while showing lower renal mRNA of SDH subunits (p<0.001) vs LD.
DD grafts showed significantly increased levels of HIF-1α (p<0.001), suggesting enhanced hypoxia status.
24 (out of 159) genes were found only in DD samples, all showing a strong correlation with HIF-1α in DD (Rho > 0.5).
Both cytokines involved in monocyte recruitment and adhesion and serum levels of pro-inflammatory IL-6 were higher in BD-DD vs HV.
Anti-inflammatory M2 proteins were significantly increased in DD monocyte protein extracts.

Conclusion

Pre-implantation inflammation assessment in DD kidneys and monitoring of circulating monocytes in transplanted patients may contribute to determine renal prognosis and improve transplantation outcome.

Funding

  • Private Foundation Support