Excerpt
It is widely accepted that the most important strategy for protection of the kidneys from shock injury and acute renal failure is preserving kidney perfusion, achieved by plasma volume expansion, maintaining cardiac output and perhaps by selectively increasing renal blood flow with drug therapy. Controversy remains as to whether volume expansion should be better achieved with a hypooncotic colloid in order to avoid kidney injury [
1]. On the one hand colloids may have a more prolonged plasma expansion effect, but, on the other, hyperoncotic colloid solutions have the potential of inducing hyperoncotic renal injury. This phenomenon was first reported with dextran use [
2]. Since then, this potential side effect has been shown with nearly all types of colloids: hydroxyethyl starch (HES) [
3], gelatins [
4] and even 20% albumin [
5], though 3% dextran 60 (as opposed to 10% dextran 40) and 5% albumin have not been associated with this syndrome. In this issue of
Intensive Care Medicine, Shortgen and co-authors [
6] test the hypothesis that hyperoncocity of volume expanders may promote renal injury. They evaluated occurrence of renal adverse events in a prospective cohort of 822 patients requiring fluid administration; these patients were divided into 4 groups: crystalloids only (127 patients), hypooncotic group [189 patients (gelatins and 4% albumin)], hyperoncotic group (401 patients/HES) and a hyperoncotic albumin group (105 patients). The occurrence of renal adverse events was more frequent in both hyperoncotic groups compared to crystalloids and normooncotic colloids, suggesting that the hyperoncocity was more relevant than the nature of the product itself. The type of HES used was a so-called modern one [130 kDa/0.4 (6%)] as well as older starches. Surprisingly, the modern 6% HES used, though expected to be less hyperoncotic, did not reduce the risk for adverse renal adverse events. Injury mechanisms remain unclear but severe concomitant dehydration and renal artery vasoconstriction are always a prerequisite [
7]. Usually, the syndrome is seen when the oncotic pressure is so high that it offsets the hydraulic pressure of glomerular filtration and, as consequence, suppresses urine output [
8]. Hyperoncotic syndrome is associated with no histological changes in most cases and it therefore stands to reason it is reversible in nature. Indeed, plasmapheresis can induce immediate recovery (as opposed to haemofiltration and haemofiltration derived therapies than cannot reverse it) [
9]. Nevertheless, some minimal histological changes, termed osmotic-nephrosis-like lesions [
9], can occur in the proximal tubule [
9] and these are seen mainly in the post kidney transplantation hyperoncotic syndrome [
10]. Controversy remains in the cardiac surgery community concerning the choice between colloids versus crystalloids and between hypo-and hyperoncotic colloids for cardiosurgery [
11]. Recently, discussion focused mainly on HES solutions, whereby the differences between HES solutions with a longer-lasting volume expansion effect [high-molecular weight (MW) and highly substituted (HES 450/0.7 or 200/0.62)] and medium MW HES solutions (HES 200/0.5, HES 130/0.4) were stressed, as medium MW HES are more easily excreted by the kidney and therefore less likely to accumulate [
12]. As the rate of renal elimination depends on the degree of hydroxyethylation of the HES molecule, the elimination half-life of the medium MW is measured in hours, whereas the elimination of larger MW could take days [
13].The question remains as to whether comorbid states (dehydration, pre-existing renal disease, diabetes mellitus, hypertension, elderly, vascular disease) may actually be more important than the type of colloid chosen [
13]. In a previous study, Shortgen and colleagues [
14] compared HES to 3% gelatin in 159 septic patients finding an odds ratio of 2.57 (95% CI: 1.13-5.83) for acute kidney injury (AKI) in case of use of HES 6% (200/0.62). However, despite randomization, the baseline creatinine was higher in the HES group as compared to the gelatin group. Furthermore, a valid criticism made at the time underlined the inadequate provision of free water in the HES group, possibly resulting in dehydration, a hyperoncotic state and subsequent compromise of renal function [
1,
9,
15,
16]. Inspite of these criticisms, this study was a well conducted randomized trial which showed that HES 6% (200/0.62) was an independent risk factor for AKI in patients with severe sepsis or septic shock [
14].The present study by Shortgen et al. [
6] has some important strengths; a large number of patients included in a well conducted study, both in terms of methodology and in terms of adjustment for confounding factors. Outcome events were pre-specified in the protocol ensuring good quality data. Nonetheless, this study also demonstrates several limitations. First, the authors did not use a recently refined definition of acute kidney injury (AKI) such as RIFLE which would make comparisons with studies both from the past and from the future easier. Secondly, concerns about adequate volume loading and correct rehydration remain, as only 527 patients out of 822 (64%) had a central venous pressure measurement available. Therefore, some patients were perhaps still dehydrated when receiving large amount of hyperoncotic colloids, which could favor the development of the hyperoncotic syndrome. When pooling the two groups of hypooncotic fluids (
n = 316) and the two groups of hyperoncotic colloids (
n = 506), the hyperoncotic pooled group appear to have a significantly higher need of fluid resuscitation (hence being more hypovolemic than the hypooncotic group) (
P value < 0.001), a significantly higher rate of organ dysfunction (
P < 0.004), a significantly higher need for vasopressors (
P < 0.003), as well as a significantly higher need for mechanical ventilation (
P < 0.001). All these conditions are known to be potentially associated with increased risk of AKI [
17]. Third, plasma oncotic pressure was not measured and accordingly occurrence of hyperoncotic syndrome cannot be proven. Finally, plasma was given to 169 patients in addition to other fluids and these are still included in the groups of patients receiving hyperoncotic colloids; 113 of 401 (28%) in the artificial hyperoncotic colloids group and 56 of 105 (53%) in the hyperoncotic albumin group. Unfortunately these patients were not analyzed as a fifth subgroup, thereby denying the authors the opportunity of eliminating this potential bias. Fresh frozen plasma contains roughly 5% albumin which is a hypooncotic colloid (therefore supposedly not harmful for the kidney) but also contains immunoglobulins which have been known to cause osmotic-nephrosis-like lesions in the proximal tubule and subsequent AKI [
18], though this relationship has not undergone a rigorous evaluation in a prospective randomized trial. Nevertheless, this large prospective cohort study published in this issue [
6] suggests strongly that hyperoncotic solutions may be harmful for the kidney. These findings are in line with those of the VISEP study [
19], which clearly demonstrated an increased risk of AKI in patients receiving HES therapy. The VISEP study was a well conducted prospective randomized trial including a large of number of patients (
N = 537). The VISEP study too was criticized [
20] for a number of reasons, in particular for a median perfusion of 2.4 l (about 34 ml/kg) of HES, which is well above the manufacturer’s recommendation of 20 ml/kg per day. Despite the fact that the authors claim they used a modern medium MW HES solution (HES 200/0.5), this 10% HES solution is nonetheless hyperoncotic (68 mm Hg), leading inevitably to a hyperoncotic syndrome. Their use of a 10% HES (200/0.5/68 mm Hg) rather than a 6% HES (200/0.5/36 mm Hg) meant a much more hyperoncotic colloid was used in comparison to the high MW 6% HES (200/0.62) used in the first Shortgen study [
14]. Another criticism leveled concerns associated risk factors; more patients in their HES group had heart failure and/or underwent emergency surgery, both associated with post-operative renal failure [
17]. Therefore, the VISEP study, although undoubtedly demonstrating that 10% HES lead to an increased risk of AKI when compared to ringer’s lactate, does not provide convincing evidence against the reasonable use of safer 6% HES (130/0.4) [
19].However, other data contradict the hypothesis that hyperoncocity alone is involved in the development of AKI. In a prospective multicentre observational study including 3,147 patients, Sakr et al. [
21] reported that HES had no influence on renal function as assessed by urine output, SOFA score, and creatinine. After multivariate analysis, HES was not associated with subsequent need for RRT. This study was criticized for a relatively low cumulative HES dosage of 1,000 ml per patient as compared to 4,550 ml in the first shortgen study [
14,
22]. Similarly, Mahmood et al. [
23], reported that renal function improved in patients undergoing abdominal surgery for aortic aneurysm receiving volume expansion with 6% HES (either 200/0.62 or 130/0.4) as compared to 4% gelatin infusion. Furthermore, although gelatin is considered a hypooncotic colloid, it too has been shown to induce hyperoncotic renal failure [
4], thereby undermining the classification on which Schortgen et al. [
6] (hypooncotic vs. hyperoncotic colloids) based their latest study. In conclusion, though this well conducted study adds very interesting new pieces of information to this already complicated puzzle, a definitive answer for the clinician as to which type of fluid he should use in case of shock, remains lacking. Exclusive use of crystalloids implies a great likelihood of edema formation with subsequent impaired gas exchange, poor wound healing and cardiac dysfunction, amongst other deleterious effects [
16]. Evidence against reasonable use of safer 6% HES(130/0.4) within the limit of the manufacturer recommendations remains inconsistent. Several randomized trials are currently ongoing [
24] and these may help us to better understand the potential role of HES in the development of AKI. …
