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Editorial: Editorials

The Effects of Hydroxyethyl Starch on Cultured Renal Epithelial Cells

Claus, Ralf A., PhD; Sossdorf, Maik, BS; Hartog, Christiane, MD

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doi: 10.1213/ANE.0b013e3181ca03a4
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The use of hydroxyethyl starch (HES) as a plasma expander in the critically ill is highly controversial.1,2 The controversy is also driven by claims that HES has properties beyond plasma expansion that are held to be beneficial in patients with sepsis, in particular, antiinflammatory properties or effects on microcirculation and oxygenation.3 The number of experimental studies supporting these claims and published by proponents of HES is growing rapidly,4–9 despite the fact that we have learned in recent years that these mechanisms are incredibly complex, and the course of sepsis is not reflected, let alone influenced, by the modulation of 1 or 2 single molecules.

In addition, evidence from large-scale studies and metaanalyses with data derived from hundreds of patients consistently confirms that such added properties of HES are clinically irrelevant because they do not contribute to improved survival in this patient population. It is becoming increasingly obvious that administration of HES is not only ineffective10–12 compared with crystalloid or other synthetic colloids in these patients, but recent evidence also shows that HES increases the incidence of renal failure in patients with severe sepsis,11,13–15 increases bleeding complications in off-pump cardiac surgery,16 and may increase overall mortality,11,15,17 and that HES-associated toxicity is dose related. Adverse effects of HES are more evident in high-quality and multicenter studies,15 but despite more than 50 years of clinical use, there is still a lack of such studies on the safety of HES in patients at risk with higher cumulative doses and longer observation periods. Moreover, little is known about the cellular mechanism of renal failure. Renal dysfunction may result from uptake of HES into proximal renal epithelial cells, resulting in so-called “osmotic nephrosis-like lesions”18 or from tubular obstruction caused by the production of hyperviscous urine. Recently, it was also observed that interstitial inflammation resulted from administration of HES in a model of isolated perfused porcine kidneys19 and that HES 200/0.5 and 130/0.4 have proinflammatory effects on platelets.20

Therefore, well-designed in vitro studies investigating the possible pathophysiologic mechanisms of HES-related toxicity are of growing interest to clinicians. This issue of Anesthesia & Analgesia includes the report of an in vitro study by Wittlinger et al.21 who evaluated the direct effects of HES 130/0.42 and HES 200/0.5 on cultured human tubular epithelial cells after pretreatment with tumor necrosis factor (TNF)-α, by measuring secretion of the monocyte chemoattractant protein-1 as a marker for inflammatory response, as well as overall cell viability and TNF-induced cell death. Unfortunately, because coincubation controls with non-HES fluids are lacking, it is impossible to determine whether the observed effects are specific for HES. It is, however, interesting to note the increased intracellular uptake of fluorescein isothiocyanate–HES (both 200/0.5 and 130/0.4) after TNF stimulation, which complies with renal biopsy findings showing colloid-filled foam cells in kidneys of patients with chronic renal failure after liver transplantation,22 and in an acute hemorrhage model in pigs.23

The study by Wittlinger et al.21 highlights the need for well-designed experimental and clinical studies with relevant end points on the subject of colloid resuscitation and especially on the role of so-called third-generation starches. Therefore, it is good news that large-scale, multicenter, randomized, controlled trials about the safety of HES are ongoing in Scandinavia and Australia.

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