Deleterious renal effects of hydroxyethyl starch 130/0.4 and 200/0.5 solutions

EDITOR:

My recent review of 92 studies, including 23 randomized clinical trials, focused on the renal impact of colloids [1]. One major conclusion from the review was that hydroxyethyl starch (HES) solutions across the full spectrum of clinically available molecular weights, substitutions and C2/C6 ratios can impair kidney function.

In comments on the review, Boldt [2] recapitulates several objections previously raised about the multicentre randomized clinical trial of 129 patients with severe sepsis or septic shock by Schortgen and colleagues [3], the largest randomized trial included in the review. Those investigators had earlier rebutted the objections [4] by noting that: (1) baseline differences affecting outcome would be unlikely due to random allocation; (2) the baseline difference in creatinine was not statistically significant; (3) the percentage of patients with renal dysfunction at baseline was actually higher in the gelatin (84%) than in the HES (75%) group, although again the difference was not statistically significant; (4) the criterion applied for acute renal failure (ARF) of a twofold serum creatinine increase might favour a group with higher baseline creatinine; and (5) ARF was the primary endpoint of the trial, which was neither designed nor powered to assess survival.

Importantly, the findings of Schortgen and colleagues [3] have now been fully confirmed by the new Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) multicentre randomized trial in 537 patients with severe sepsis or septic shock [5]. That trial compared morbidity and mortality in patients receiving an HES solution of 200 kDa molecular weight and 0.5 M substitution (HES 200/0.5) to a maximum of 20 mL kg⁻¹ day⁻¹ or Ringer’s lactate control fluid. HES 200/0.5 increased both the incidence of ARF compared with that in the control group (34.9% vs. 23.2%; P = 0.003) and the frequency of renal replacement therapy (31.0% vs. 18.8%; P = 0.001). A trend towards higher mortality was also observed in the HES 200/0.5 group (41.0% vs. 33.9%; P = 0.09).

Boldt and colleagues [6] also recapitulate the interpretation they had placed on their randomized trial showing renal impairment after pump priming and volume expansion with HES 130/0.4 or gelatin in elderly cardiac-surgery patients. They argued that since both groups displayed renal impairment, and gelatin is devoid of adverse effects on the kidney, the observed deleterious renal effects may have been due to cardiopulmonary bypass itself rather than due to the fluid regimen. As detailed in my review, this argument proceeds from a flawed premise, because of randomized trial evidence that in fact gelatin does impair renal function compared with albumin [7,8]. Another commentator on this trial of Boldt and colleagues has also reached the conclusion that their data demonstrate renal impairment attributable to HES 130/0.4 [9].

Finally, Boldt contends that further reviews on volume replacement are not needed, even though he himself has been a prolific author of such reviews [10–12]. I disagree with this. Reviews serve the valuable aim of assembling and critically appraising evidence arising from a profuse and rapidly expanding clinical research literature. Reviews can also generate testable hypotheses. For example, the Cochrane albumin meta-analysis [13] motivated the Saline vs. Albumin Fluid Evaluation (SAFE) randomized trial [14]. Fluid-management strategies remain the subject of intensive investigation. Consequently, timely reviews will continue to play a key role in assimilating this growing body of evidence and in arriving at sound conclusions that can be incorporated into clinical practice.