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Selected Publication:
Feuchter, V.
Immune dysfunction in chronic kidney disease
Humanmedizin; [ Diplomarbeit ] Graz Medical University; 2018. pp.94.
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- Authors Med Uni Graz:
- Advisor:
- Leber Bettina
- Stadlbauer-Köllner Vanessa
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- Abstract:
- Background: Patients with renal disease experience volume overload and dialysis induced haemodynamic changes leading to alternating splanchnic hyper- and hypoperfusion. Dietary restrictions and the translocation of retained uremic toxins to the gut change the intestinal microbiota in a way, which cannot contribute to intestinal barrier integrity anymore. The consequences are intestinal barrier disruption and endotoxin (LPS) translocation to the blood. Systemic LPS stimulates neutrophils to release reactive oxidative species (ROS) and cytokines and thereby induces chronic inflammation and oxidative stress. Cytokines, ROS and LPS itself interact with the endothelial membrane and induce early steps of cardiovascular disease (CVD). An overstimulation of neutrophils might be linked to cellular dysfunction and subsequent reduced pathogen defence. Moreover, patients with renal disease suffer from PEW, which describes an imbalance between protein intake and protein loss. Low albumin levels, because of PEW, and oxidation of residual albumin via LPS results in reduced albumin mediated scavenging of ROS. The combination between repeated LPS translocation, oxidative stress, neutrophil activation and dysfunction leads to chronic inflammation, high risk for infections and CVD in patients with renal disease. Aims: The aims of this thesis were to test 1) whether patients with renal disease show signs for inflammation, PEW and have elevated biomarkers for CVD, 2) whether the serum induced bacterial growth retardation capacity differs between patients with renal disease and healthy controls, 3) whether LPS influences the phagocytosis of in vitro differentiated neutrophil like leukaemia cells (HL-60 cells). Materials and methods: Laboratory parameters were collected during the “endotoxin, neutrophil function and albumin in renal insufficiency” (ENARI) study and retrospectively analysed during this thesis. To assess alterations in the immune system, levels of LPS, LPS binding proteins, immune cells, albumin, cytokines and C-reactive protein were analysed. To determine the risk for CVD, the biomarkers neutrophil:lymphocyte and C reactive protein:albumin ratio were assessed. To determine the extent of PEW, total plasma protein and cholinesterase levels were analysed. We used a newly developed biomarker, which predicted infections in patients with liver cirrhosis, in this study cohort. Therefore, we determined the capacity of patient sera to inhibit growth of Escherichia coli. Furthermore, we assessed the effect of 250 and 500 ng/ml LPS on the phagocytosis of in vitro differentiated neutrophil like HL-60 cells by Phagotest®. Results: All patients had significantly higher blood LPS levels and an elevated inflammatory state, confirmed by elevated cytokine and LPS-binding protein levels. All patients had a significantly higher risk for CVD, as all patients showed higher neutrophil:lymphocyte. All patients had a higher risk for PEW, confirmed by reduced cholinesterase levels, albumin and total plasma protein. All patients had a higher serum mediated bacterial growth retardation compared to healthy controls. The phagocytic capacity and the percentage in phagocytosing neutrophil-like differentiated HL-60 cells was higher at higher levels of LPS, suggesting that LPS at this concentration stimulates phagocytosis. Conclusion: We conclude that patients with renal disease have an increased immune activity, systemic LPS concentration and an increased risk for CVD and PEW. We conclude that further studies about the applicability of the newly developed biomarker, which predicted infections in patients with liver cirrhosis, must be done in patients with renal disease. We conclude that LPS at a concentration of 500 ng/ml has a stimulating effect on the phagocytosis of in vitro differentiated neutrophil like HL-60 cells. Nevertheless, further studies about the effect of LPS on neutrophils in patients with renal disease are required.