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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.


1. Boldt J. PRO: hydroxyethylstarch can be safely used in the intensive care patient—the renal debate. Intensive Care Med 2009;35:1331–6
2. Hartog C, Reinhart K. CONTRA: Hydroxyethyl starch solutions are unsafe in critically ill patients. Intensive Care Med 2009;35:1337–42
3. Vincent JL. The pros and cons of hydroxyethyl starch solutions. Anesth Analg 2007;104:484–6
4. Nohe B, Johannes T, Reutershan J, Rothmund A, Haeberle HA, Ploppa A, Schroeder TH, Dieterich HJ. Synthetic colloids attenuate leukocyte-endothelial interactions by inhibition of integrin function. Anesthesiology 2005;103:759–67
5. Tian J, Lin X, Zhou W, Xu J. Hydroxyethyl starch inhibits NF-kappaB activation and prevents the expression of inflammatory mediators in endotoxic rats. Ann Clin Lab Sci 2003;33:451–8
6. Feng X, Yan W, Liu X, Duan M, Zhang X, Xu J. Effects of hydroxyethyl starch 130/0.4 on pulmonary capillary leakage and cytokines production and NF-kappaB activation in CLP-induced sepsis in rats. J Surg Res 2006;135:129–36
7. Lv R, Zhou ZQ, Wu HW, Jin Y, Zhou W, Xu JG. Hydroxyethyl starch exhibits antiinflammatory effects in the intestines of endotoxemic rats. Anesth Analg 2006;103:149–55
8. Matharu NM, Butler LM, Rainger GE, Gosling P, Vohra RK, Nash GB. Mechanisms of the anti-inflammatory effects of hydroxyethyl starch demonstrated in a flow-based model of neutrophil recruitment by endothelial cells. Crit Care Med 2008;36:1536–42
9. Volta CA, Alvisi V, Campi M, Marangoni E, Alvisi R, Castellazzi M, Fainardi E, Manfrinato MC, Dallocchio F, Bellini T. Influence of different strategies of volume replacement on the activity of matrix metalloproteinases: an in vitro and in vivo study. Anesthesiology 2007;106:85–91
10. Wills BA, Nguyen MD, Ha TL, Dong TH, Tran TN, Le TT, Tran VD, Nguyen TH, Nguyen VC, Stepniewska K, White NJ, Farrar JJ. Comparison of three fluid solutions for resuscitation in dengue shock syndrome. N Engl J Med 2005;353:877–89
11. Brunkhorst FM, Englel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–39
12. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2007;CD000567
13. Schortgen F, Lacherade JC, Bruneel F, Cattaneo I, Hemery F, Lemaire F, Brochard L. Effects of hydroxyethylstarch and gelatin on renal function in severe sepsis: a multicentre randomised study. Lancet 2001;357:911–6
14. Hagne C, Schwarz A, Gaspert A, Giambarba C, Keusch G. HAES in septic shock—sword of Damocles? Schweiz Med Forum 2009;9:304–6. Available at:
15. Zarychanski R, Turgeon AF, Fergusson DA, Cook DJ, Hebert P, Bagshaw SM, Monsour D, McIntyre LA. Renal outcomes and mortality following hydroxyethyl starch resuscitation of critically ill patients: systematic review and meta-analysis of randomized trials. Open Med 2009;3:E196–209
16. Hecht-Dolnik M, Barkan H, Taharka A, Loftus J. Hetastarch increases the risk of bleeding complications in patients after off-pump coronary bypass surgery: a randomized clinical trial. J Thorac Cardiovasc Surg 2009;138:703–11
17. Sedrakyan A, Gondek K, Paltiel D, Elefteriades JA. Volume expansion with albumin decreases mortality after coronary artery bypass graft surgery. Chest 2003;123:1853–7
18. Dickenmann M, Oettl T, Mihatsch MJ. Osmotic nephrosis: acute kidney injury with accumulation of proximal tubular lysosomes due to administration of exogenous solutes. Am J Kidney Dis 2008;51:491–503
19. Huter L, Simon TP, Weinmann L, Schuerholz T, Reinhart K, Wolf G, Amann KU, Marx G. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model. Crit Care 2009;13:R23
20. Sossdorf M, Appelt A, Schaarschmidt B, Döring S, Claus RA, Hartog C, Lösche W. Hydroxyethyl starch solutions impair clot formation and platelet aggregation but enhance platelet surface receptor expression. Hämatologie 2008;28:A82
21. Wittlinger M, Schlaefer M, De Conno E, Roth Z'graggen B, Reyes L, Booy C, Seifert B, Burmeister MA, Spahn D, Beck-Schimmer B. The effect of hydroxyethyl starches (HES 130/0.42 and HES 200/0.5) on activated renal tubular epithelial cells. Anesth Analg 2010;110:531–40
22. Pillebout E, Nochy D, Hill G, Conti F, Antoine C, Calmus Y, Glotz D. Renal histopathological lesions after orthotopic liver transplantation (OLT). Am J Transplant 2005;5:1120–9
23. Eisenbach C, Schonfeld AH, Vogt N, Wente MN, Encke J, Stremmel W, Martin E, Pfenninger E, Weigand MA. Pharmacodynamics and organ storage of hydroxyethyl starch in acute hemodilution in pigs: influence of molecular weight and degree of substitution. Intensive Care Med 2007;33:1637–44
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