Title: The significance of innate immune response in kidney transplantation and evaluation of inflammatory markers

Main supervisor: Alireza Biglarnia

Reviewers: Gunnar Sterner & Josefina Dykes

Abstract

Background

Ischemia-reperfusion injury (IRI) continues to pose a significant burden on transplant outcomes. Recent preclinical research highlights the crucial involvement of innate immunity during IRI. However, the implications of IRI-induced innate immune activation on clinical kidney transplant (KT) outcomes remain unclear.

Research questions

The ongoing project comprises multiple clinical studies aimed at characterizing the initial innate immune response triggered by IRI and investigating its effects on transplant outcomes.

Preliminary results

Project 1: Among 63 KT recipients, a prompt thrombo-inflammatory response following reperfusion was observed in DD kidneys, correlating to short- and mid-term graft dysfunction. The use of hypothermic machine perfusion was associated with mitigated thromboinflammation and maintained mid-term kidney function.

Project 2: Assessment of 92 inflammatory markers using proteomics on the Project 1 cohort revealed increased levels of several inflammatory proteins in DD kidneys compared to LD kidneys following reperfusion. Ongoing evaluation assesses their predictive value concerning short- and long-term transplant outcomes.

Project 3: In 29 KT recipients, flow cytometry assessing dynamics on immune cell levels during the initial phase of IRI identified the involvement of intermediate and non-classical monocytes along with CD25+CD8+ T cells during the immediate phase of allograft reperfusion.

Project 4: In 133 KT recipients, a novel highly specific C4d detection antibody was assessed against the less specific antibody currently used as standard of care for rejection diagnostics. Peri-rejection C4d plasma levels showed inconclusive correlations with simultaneous rejection. A discordance was observed between the two antibodies regarding C4d detection in allograft-biopsies obtained during rejection. Further analyses are ongoing to verify this important finding.

Project 5: Samples from 127 KT recipients were assessed for cell-free DNA, a marker for cell injury. Following reperfusion, DD kidneys consistently exhibited elevated nuclear cell-free (n-cf) DNA levels compared to LD, mirroring the inflammatory response pattern observed in projects 1 and 2. Furthermore, n-cfDNA release was associated with short-term graft dysfunction.

Significance

Our results deepen the understanding of initial inflammation during KT and its implications for patient outcomes. This insight may lead to the identification of new surrogate markers and potentially foster the development of new therapeutic strategies aimed at optimizing KT outcomes.

Published studies

Paper 1: Strandberg G, et al. Prompt Thrombo-Inflammatory Response to Ischemia-Reperfusion Injury and Kidney Transplant Outcomes. Kidney Int Rep. 2023 Sep 24;8(12):2592-2602. doi: 10.1016/j.ekir.2023.09.025. PMID: 38106604; PMCID: PMC10719603.