Inflammatory Kidney and Liver Tissue Response to Different Hydroxyethylstarch (HES) Preparations in a Rat Model of Early Sepsis

Abstract

BackgroundTissue hypoperfusion and inflammation in sepsis can lead to organ failure including kidney and liver. In sepsis, mortality of acute kidney injury increases by more than 50%. Which type of volume replacement should be used is still an ongoing debate. We investigated the effect of different volume strategies on inflammatory mediators in kidney and liver in an early sepsis model.Material and MethodsAdult male Wistar rats were subjected to sepsis by cecal ligation and puncture (CLP) and assigned to three fluid replenishment groups. Animals received 30mL/kg of Ringer’s lactate (RL) for 2h, thereafter RL (75mL/kg), hydroxyethyl starch (HES) balanced (25mL/kg), containing malate and acetate, or HES saline (25mL/kg) for another 2h. Kidney and liver tissue was assessed for inflammation. In vitro rat endothelial cells were exposed to RL, HES balanced or HES saline for 2h, followed by stimulation with tumor necrosis factor-α (TNF-α) for another 4h. Alternatively, cells were exposed to malate, acetate or a mixture of malate and acetate, reflecting the according concentration of these substances in HES balanced. Pro-inflammatory cytokines were determined in cell supernatants.ResultsCytokine mRNA in kidney and liver was increased in CLP animals treated with HES balanced compared to RL, but not after application of HES saline. MCP-1 was 3.5fold (95% CI: 1.3, 5.6) (p<0.01) and TNF-α 2.3fold (95% CI: 1.2, 3.3) (p<0.001) upregulated in the kidney. Corresponding results were seen in liver tissue. TNF-α-stimulated endothelial cells co-exposed to RL expressed 3529±1040pg/mL MCP-1 and 59±23pg/mL CINC-1 protein. These cytokines increased by 2358pg/mL (95% CI: 1511, 3204) (p<0.001) and 29pg/ml (95% CI: 14, 45) (p<0.01) respectively when exposed to HES balanced instead. However, no further upregulation was observed with HES saline. PBS supplemented with acetate increased MCP-1 by 1325pg/mL (95% CI: 741, 1909) (p<0.001) and CINC-1 by 24pg/mL (95% CI: 9, 38) (p<0.01) compared to RL. Malate as well as HES saline did not affect cytokine expression.ConclusionWe identified HES balanced and specifically its component acetate as pro-inflammatory factor. How important this additional inflammatory burden on kidney and liver function is contributing to the sepsis-associated inflammatory burden in early sepsis needs further evaluation.

6% Hydroxyethyl starch (HES 130/0.4) diminishes glycocalyx degradation and decreases vascular permeability during systemic and pulmonary inflammation in mice

“…Causative approaches to explaining these findings remain scarce. Lately, acetate as a common component of available HES formulations has been shown to act as a proinflammatory factor during systemic inflammation in rats [ 57 ]. Furthermore, a recent study showed that high dosages (50 ml/kg) of HES 130/0.4 cause deterioration of kidney function in otherwise healthy rats [ 58 ].…”

Association Between Urinary Alpha1-Microglobulin Levels and Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

“…The steatotic hepatocytes may be a more important source of proinflammatory cytokines resulting from altered lipid and immune homeostasis [37-39]. Furthermore, a heterogeneous class of hepatokines such as plasminogen activator inhibitor-1 and tumor necrosis factor-α can modulate reversed renal lipid accumulation, glomerular sclerosis, and tubulointerstitial inflammation [40-42]. …”

Haemodilution and head-down tilting induce functional injury in the rat optic nerve

“…For isovolumic haemodilution, 2-ml blood was withdrawn from the venous catheter every 30 min over a 90-min period; during this time the animals remained positioned according to group assignment. Blood was replaced with 6% Hetastarch (Hospira, Lake Forest, Illinois, USA) 12 following each 2-ml blood withdrawal, until target haematocrit (approximately 40% reduction) was achieved.…”