Targeting the NLRP3 Inflammasome during Normothermic Machine Perfusion to augment the Viability of Aged Kidneys for Transplant

• Applicant: Dr. Philipp Tessmer
• Subject Area: General and Visceral Surgery
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 584278587

The project investigates why kidneys from older organ donors are particularly susceptible to ischemia-reperfusion injury (IRI) in renal transplantation. IRI is a central and inevitable consequence of organ transplantation that compromises both early graft function and long-term graft survival. Due to the persistent organ shortage, an increasing reliance on older organ donors has become clinical reality: in 2024, more than one-third of all brain-dead organ donors in Germany were at least 65 years old, despite their heightened vulnerability to IRI. The NLRP3 inflammasome – a multi-protein complex activated by danger-associated molecular patterns – has emerged as a key mediator of renal IRI during transplantation because it drives sterile inflammation and induces pyroptosis (from Greek "pyro" = fire and "ptosis" = death), a highly inflammatory form of programmed cell death. Compelling experimental evidence from mouse models shows that aging upregulates NLRP3-pyroptosis signaling thereby substantially exacerbating IRI. In our experimental preliminary work, we identified proinflammatory mediators of this pathway in a preclinical animal model that contribute to organ injury during normothermic machine perfusion (NMP) of porcine livers. NMP is a dynamic preservation technique that perfuses donor organs ex vivo at 37°C with a blood-based perfusate. It allows for organ viability assessment under near-physiological conditions before transplantation and is increasingly recognized as a promising therapeutic platform for ex vivo organ reconditioning. The project pursues three overarching goals: 1. Dissect age-dependent NLRP3 signaling pathways in vivo: Using unique murine transplantation models, we will delineate the impact of aging on NLRP3 inflammasome activation in renal ischemia reperfusion injury by comparing transplant outcomes between young and old donor kidneys. 2. Analyze NLRP3-inflammasome activation driving sterile inflammation during NMP: In an established murine NMP model, we will identify age-dependent drivers of sterile inflammation during ex vivo kidney perfusion and target them specifically in subsequent experiments using neutralizing antibodies. 3. Evaluate therapeutic ex vivo organ reconditioning in a murine transplantation model: The most promising anti-inflammatory interventions will be applied during NMP to improve the viability of aged kidneys for transplantation. These reconditioned organs will then be transplanted to demonstrate, for the first time, protective effects of ex vivo organ reconditioning on organ injury and graft function. The long-term goal is to "rescue" old donor organs through the development of novel NMP-based therapeutic strategies and to redefine aging as an opportunity in transplantation – ultimately aiming to reduce the gap between organ demand and supply.

• DFG Programme: Fellowship
• International Connection: USA
• Host: Professor Stefan Tullius, Ph.D.