Colloids and improvement of renal function

teaser

David Faraoni MD
Philippe Van der Linden MD PhD
Department of Anaesthesiology,
Centre Hospitalier Universitaire Brugmann, HUDERF, Brussels,
Belgium

Acute kidney dysfunction (AKD) is one of the most common hospital-acquired complications, and severely ill patients frequently experience this complication. Its occurrence is associated with higher rates of gastrointestinal bleeding, respiratory infections and sepsis, leading to increase length of intensive care unit (ICU) and hospital stay, and increased hospitalisation costs.(1) Different risk factors are responsible for AKD: patient co-morbidities; systemic inflammation; haemodynamic impairment; and direct toxic injuries. However, hypoperfusion episodes are found in most cases of AKD and 80% of patients with postoperative renal impairment have a previous perioperative episode of haemodynamic instability.(2) The kidney receives 20-25% of total cardiac output (CO) and, among the different renal regions, the medullary portion of the nephrons is at high risk for hypoperfusion. Decrease in CO will lead to kidney hypoperfusion and will also activate neurohumoral responses, which leads to renal vasoconstriction.

To date, no specific targeted treatment has been evaluated to improve renal function and the maintenance of an optimal kidney perfusion remains the most important prophylactic measure to protect renal function. To achieve this goal, CO has to be maintained in order to match the increase oxygen consumption related to illness. For this reason, adequate volaemia has to be maintained. Actually, it has not yet been shown that a liberal infusion regimen decreases the liberal infusion regimen would decrease the incidence of AKD. A goal-directed approach has to be preferred to decrease side-effects associated with fluid overload.

Haemodynamic optimisation
Although there is increasing evidence that haemodynamic optimisation in high-risk surgical patients can reduce postoperative mortality and morbidity, studies that evaluate the effect of this strategy on AKD are rare. This could be explained by the difficulty in defining AKD. Indeed, clinical AKD manifestations vary between oliguria and renal replacement therapy (RRT) and not all markers of AKD may have the same clinical impact. The RIFLE score has been implemented in clinical and research practices, with the aim of standardising the interpretation of AKD. This score uses glomerular filtration rate (GFR), serum creatinine and urine output (UO) to define three grades of severity (risk, injury, and failure) and two outcome classes (loss; end-stage kidney disease).(3) In 2009, Brienza et al(4) published a meta-analysis on the effect of perioperative haemodynamic optimisation on postoperative AKD. In their analysis, patients receiving perioperative haemodynamic optimisation experienced less renal impairment. They showed that peroperative or immediate postoperative optimisation is as effective as preoperative intervention.

Manipulations performed during or soon after injury might represent adequate alternatives when preoperative (pre-injury) approaches cannot be realised. However, studies included in their analysis did not permit an adequate evaluation of the effects of fluid loading on the incidence of postoperative AKD. Indeed, only observational studies and a small number of patients were included, whereas well-designed studies are needed to evaluate the effect of fluid management on the incidence of AKD. Moreover, only a goal-directed strategy could lead to adequate conclusion in terms of risk-benefit balance. Unanswered questions concern which fluid could present the best profile in this setting and what is the relative contribution of fluids and catecholamine administration to the improvement of oxygen delivery.

In 2010, the Critical Care Nephrology Working Group issued from the European Society of Intensive Care Medicine (ESCIM) critically reviewed strategies aiming at preventing AKD or protecting renal function in the ICU.(5) Both relative and overt hypovolaemia are significant risk factors for the development of AKD. As a consequence, they recommended controlled fluid resuscitation in true or suspected volume depletion (Grade 1C) to improve renal function and prevent AKD.

Effect of colloids on renal function
Different types of fluid can be used to maintain an adequate circulating blood volume and optimise CO. Some physiological considerations have to be taken into account. Physiological fluid shifting from the vessel to the interstitial space across an intact vascular barrier contains only small amounts of protein and small molecules. It does not lead to interstitial oedema provided it can be quantitatively managed by the lymphatic system. Once the lymphatic drainage becomes overpassed, fluids remain in the interstitial space and result in oedema formation. In contrast to crystalloids, which freely cross the intact vasculature wall, colloids would stay within the vascular space. Optimisation of CO would therefore require less colloid than crystalloids. Infusion of large amounts of crystalloid are associated with significant interstitial oedema, which  may result in increased postoperative mortality and morbidity.(6)
Different colloids have been studied. The only natural colloid used in clinical practice is albumin. Under physiological conditions, albumin is the protein responsible for the intravascular oncotic pressure and should therefore be considered as the ideal fluid for volume replacement. However, it may cause allergic reactions and immunological complications. The SAFE study compared albumin with saline for fluid resuscitation in ICU patients. This large study did not shown any beneficial effect on mortality and morbidity, specifically on the need of RRT.(7) Moreover, its higher price does not make this solution the first choice for routine fluid replacement.

The two synthetic colloids used in daily practice are gelatins and hydroethyl starches (HES). Gelatins are small macromolecules obtained from the degradation of collagen. Their intravascular persistence is approximately two hours, and 30% of the infused volume will be redistributed to the interstitium. Anaphylactic reaction remains the major side effect associated with their use. HES represent a family of different colloid solutions, which vary with regard to concentration, molecular weight, molar substitution and C2/C6 ratio. In addition, these solutions can be prepared with either a balanced or a non-balanced electrolytes solvent. Although their physicochemical characteristics do not seem to influence their plasma expending properties, they significantly influence their side-effect profile. The newest generation of these products (tetrastarches) has demonstrated comparable volume expansion effects to older starches but with fewer undesirable effects.

Conflicting studies have been published about the safety of the different solutions in terms of kidney function. All colloids, when administered without crystalloids in the dehydrated patients, might result in hyperoncotic acute renal failure owing to the generation of a high plasma oncotic pressure, which counteracts the hydraulic pressure gradient in the glomerulus.(8) In addition, HES solution can be reabsorbed into renal tubular cells, leading to osmotic nephrotic lesions. This effect appears related to the in vivo molecular weight of the starches that determined tissue accumulation and toxicity.

The controversial effects of starches on renal function need to take into account several factors. First, different populations have been studied and cannot be compared adequately. Indeed, ICU patients are exposed to severe inflammatory reactions and haemodynamic instability that can contribute to increased risk of AKD independently of the resuscitation fluid used. Second, it is important to distinguish studies that used older generations of hyperoncotic starches (10% HES 200/0.5) without regard to doses limitations(9) from those evaluating newest generation of starches with the respect of dose limitation.(10) In addition, the SOAP study, including more than 3000 critically ill septic patients treated with pentastarches and tetrastarches, showed no greater risk of AKD with these solutions in comparison to other colloids or crystalloids.(11)

Finally, the incidence of AKD has rarely been chosen as the primary end-point in a well-designed randomised controlled trial. For this reason, results need to be interpreted with caution and by taking into account the strategy (timing, volume, monitoring) used in the different studies to guide fluid administration.

Several studies have focused more specifically on the effect of the latest generation of colloids on renal function. James et al(12) showed that, in trauma patients, 6% HES 130/0.4 provided significantly better lactate clearance and less renal injury than saline. Simon  and colleagues13 compared 6% HES 130/0.42 and 4% modified gelatin both balanced in acetate solution with 10% HES 200/0.5 in saline and Ringer’s acetate (RAc) in a two-hit model of shock. They showed that, despite similar maintenance of microcirculation, 6% HES 130/0.42 and RAc significantly preserve renal function and attenuate tubular damage better that 10% HES 200/0.5 in saline. Aksu et al(14) observed similar results in an animal study during endotoxaemic shock. HES 130/0.42 in saline was compared with HES 130/0.42 in RAc in terms of macrocirculatory and microcirculatory perfusion of the kidney. They showed that even if both HES solutions improved hemodynamic parameters, only HES 130/0.42 in RAc improved renal artery blood flow and microvascular renal perfusion.

Finally, as reported in a recent meta-analysis, the actual published studies report too few events to estimate reliably the risks or benefits associated with the use of 6% HES 130/0.4.15 In the near future, the crystalloid versus hydroxyethyl starch trial (CHEST) will be published (ClinicalTrials.gov Identifier: NCT00935168). This multi-centre, randomised controlled trial involves 7000 patients and compares the effect of 6% HES 130/0.4 with normal saline on day-90 morbidity and mortality in patients receiving the fluid for resuscitation in medical and surgical ICU. The results of this study will certainly contribute to a better understanding of the risk-benefit ratio of using 6% HES 130/0.4 in severely ill patients.

Conclusions
Haemodynamic stability plays a pivotal role in the prevention of AKD in severely ill patients. Circulating blood volume optimisation is certainly the first line of treatment to maintain renal perfusion and decrease the risk of renal failure. Colloids are clearly more efficacious than crystalloids for this purpose; however, there is no actual evidence that one solution may be better than another. Tetrastarches have presented interesting pharmacokinetic and pharmacodynamic properties. On the one hand, they allow efficacious volume expending effect and possible beneficial effect on the microcirculation. On the other, their low in vivo molecular weights result in markedly reduced tissue accumulation and therefore decrease the incidence of side effects. The advantageous profile of tetrastarches should be confirmed by the forthcoming results of the CHEST study.

References

1. Dimick JB et al. Complications and costs after high-risk surgery: where should we focus quality improvement initiatives? J Am Coll Surg 2003;196:671–78.
2. Tang IY, Murray PT. Prevention of perioperative acute renal failure: what works? Best Pract Res Clin Anaesthesiol 2004;18:91–111.
3. Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007;33:409–13.
4. Brienza N et al. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study. Crit Care Med 2009;37:2079–90.
5. Joannidis M et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM. Intensive Care Med 2010;36:392–411.
6. Lowell JA et al. Postoperative fluid overload: not a benign problem. Crit Care Med 1990;18:728–33.
7. Finfer S et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–56.
8. Moran M, Kapsner C. Acute renal failure associated with elevated plasma oncotic pressure. N Engl J Med 1987;317:150–3.
9. Brunkhorst FM et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 2008;358:125–39.
10. Sakr Y et al. Time course and relationship between plasma selenium concentrations, systemic inflammatory response, sepsis, and multiorgan failure. Br J Anaesth 2007;98:775–84.
11. Sakr Y et al. Effects of hydroxyethyl starch administration on renal function in critically ill patients. Br J Anaesth 2007; 98:216–24.
12. James MF et al. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth 2011;107:693–702.
13. Simon TP et al. Impairment of renal function using hyperoncotic colloids in a two hit model of shock: a prospective randomized study. Crit Care 2012;16:R16.
14. Aksu U et al. Acute effects of balanced versus unbalanced colloid resuscitation on renal macrocirculatory and microcirculatory perfusion during endotoxemic shock. Shock 2012;37:205–209.
15. Gattas DJ et al. Fluid resuscitation with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and meta-analysis. Anesth Analg 2012;114:159–69.