Differential Cytokine Levels during Normothermic Kidney Perfusion with Whole Blood- or Red Blood Cell-Based Perfusates—Results of a Scoping Review and Experimental Study

Abstract

The ideal composition of the perfusate for normothermic kidney perfusion is unknown, though the perfusate commonly used to perfuse human kidneys contains leukocyte-depleted packed red blood cells (RBC), as this is believed to prevent excessive inflammation. We performed a systematic search identifying 19 articles reporting on cytokine levels during normothermic pig or human kidney perfusion. Cytokine levels varied widely across the reported studies. No direct comparisons of perfusate cytokines during perfusion with RBC or whole blood were performed, and no data on how these levels are influenced by ischemia are available. Therefore, we compared perfusate IL-6, IL-1β, TNF-α, TGF-β, IL-10, IL-8, and CCL2 levels during 4 h normothermic pig kidney perfusion with a whole blood- or RBC-based perfusate. Kidneys were exposed to either 1 h of warm or 22 h of cold ischemia. We found no evidence of different perfusate cytokine or gene expression levels in whole blood or RBC perfusions. There was no clear evidence to suggest that cytokine concentrations differ between ischemically injured kidneys and controls. In conclusion, pro-inflammatory and anti-inflammatory cytokines and chemokines are detectable in the perfusate and urine of kidneys undergoing normothermic perfusion. It is unclear how cytokine levels change in different ischemic conditions and whether the use of a leukocyte filter plays a role.

Ischemia-Induced Metabolic Patterns Associate With Kidney Function During Normothermic Kidney Perfusion, a Preclinical Study

“…Although not the study’s focus, we found no clear evidence suggesting whole blood perfusion, commonly though, to lead to increased inflammation and injury because of white cells and platelets, is worse than RBC perfusion. We reported earlier that little evidence suggests a difference in perfusate cytokine concentrations between whole blood and RBC perfusions which might explain similar clinical read-outs 43 . Tissue-resident immune cells, abundantly present in the kidney, are released in the perfusate during normothermic perfusion, and these likely play a part in the observed inflammatory response 44–46 …”

“…We reported earlier that little evidence suggests a difference in perfusate cytokine concentrations between whole blood and RBC perfusions which might explain similar clinical read-outs. 43 Tissue-resident immune cells, abundantly present in the kidney, are released in the perfusate during normothermic perfusion, and these likely play a part in the observed inflammatory response. [44][45][46]…”

Taurine as Antioxidant in a Novel Cell- and Oxygen Carrier-Free Perfusate for Normothermic Machine Perfusion of Porcine Kidneys

“…However, IL-6 levels need to be interpreted cautiously, as it has both pro- and anti-inflammatory properties [ 40 , 41 , 42 ]. Recently, De Beule et al found that the cytokine levels between kidneys perfused with whole blood and those perfused with pRBCs did not differ significantly [ 43 ]. As pRBCs are deprived of leukocytes, one would assume that the inflammatory response is milder in comparison to whole blood.…”

How to Best Protect Kidneys for Transplantation—Mechanistic Target

“…A recent systematic review by De Beule et al found that during machine perfusion, perfusate cytokine levels are similar in kidneys perfused with whole blood compared to kidneys perfused with leukocyte-depleted packed red blood cells [142]. This demonstrates that kidney tubular epithelial cells and the resident immune cells can produce large amounts of cytokines and chemokines, which can upregulate inflammatory pathways within the graft before implantation and independently of the presence of an immune system.…”