Vasopressors are the mainstay of therapy in vasodilatory shock: Noradrenalin is the preferred choice over adrenaline or dopamine given they are associated with higher rates of arrhythmias [2, 3]. Vasopressin may be an option in vasoplegic states where noradrenalin use fails to attain target values and some recent studies suggest a lower incidence of AKI stage 1 when vasopressin rather than noradrenalin is used [4].

Where reduced cardiac output predominates the clinical picture, inotropic agents including inodilators are a reasonable option. Interestingly, recent data indicates that the calcium sensitizers levosimendan may be superior with regard to effects on renal function compared to dobutamine especially in the setting of sepsis [5, 6].

Both relative and overt hypovolaemia contribute to reduced cardiac filling pressures and potentially lead to reduced renal perfusion and therefore timely, appropriate fluid administration is a preventive measure which should be effective both through the restoration of the circulating volume and potentially minimising drug induced nephrotoxicity [7]. Where volume replacement is indicated this should be performed in a controlled fashion directed by hard end points with hemodynamic monitoring [8] as injudicious use of fluids carries its own inherent risk [9] (see below).

Volume replacement may employ 5 % glucose (i.e. free water), crystalloids (isotonic, half isotonic), colloids or a combination thereof. Glucose solutions substitute free water and are mainly used to correct hyperosmolar states. Given free water is distributed throughout the extracellular volume, glucose solutions provide only about half of the effects on volume expansion as compared to crystalloids. Isotonic crystalloids represent the mainstay for correction of extracellular volume depletion. However, increased chloride load resulting from normal saline may result in a hyperchloraemic acidosis and potential renal vasoconstriction as well as altered perfusion of other organs such as the gut [10]. Recent investigations suggest increased risk of AKI and RRT as well as increased mortality associated with use of large volumes of 0.9 % saline as compared to so called ‘balanced solutions’ which contain significantly lower chloride concentrations [11–13]. However, to-date there are no published randomised controlled studies comparing saline to balanced solutions and the effects on renal function and recent evidence suggest that other cofounders may also play a role in the development of AKI. Whereas crystalloids expand plasma volume by approximately 25 % of the infused volume, colloid infusion results in a greater expansion of plasma volume. The degree of expansion is dependent on concentration, mean molecular weight and (for starches) the degree of molecular substitution. Furthermore, volume effects of colloids are dependent on the integrity of the vascular barrier which is often compromised in the presence of a severe SIRS response as well as sepsis. Artificial colloids used clinically include gelatines, starches and dextrans. Human albumin (HA) is the only naturally occurring colloid with additional pleiotropic properties outside the scope of this chapter.

Hydroxyethyl starches (HES) are highly polymerised non-ionic sugar molecules characterised by molecular weight, grade of substitution, concentration and C2/C6 ratio. Their volume effect is greater than that of albumin especially when larger sized polymers are employed. These molecules degrade through hydrolytic cleavage the products of which undergo renal elimination. However, these degradation products may be reabsorbed and contribute to osmotic nephrosis and possibly medullary hypoxia [14–16]. A further problem with HES may be dose dependant tissue deposition and associated pruritus [17–19] which appear to be characteristic for all preparations of HES independent of molecular size and substitution grade. Recent randomized controlled trials (RCT) have substantiated increased risk for AKI and renal replacement therapy by using starches especially in sepsis [20–22] leading to the recommendation not to use starches in critically ill patients [23, 24]. Gelatines have an average molecular weight of ca. 30 KD and the observed intravascular volume effect is shorter than that observed with HA or HES although potential side effects of there use include the possibility of prion transmission, histamine release and coagulation problems particularly with the use of large volumes [25, 26]. Furthermore, there is a theoretical risk of osmotic nephrosis with gelatine use although data is scarce and studies fail to demonstrate any deleterious effects on renal function as determined by changes in serum creatinine [27–29]. Dextrans are single chain polysaccharides comparable to albumin in size (40–70 kDa) and with a reasonably high volume effect though again anaphylaxis, coagulation disorders and indeed AKI may occur at doses higher than 1.5 g/kg/day [30–33]. Osmotic nephrosis has also been reported for dextranes [16].

HA may appear attractive in hypooncotic hypovolaemia but in some countries is costly [34–36]. A large multicenter RCT comparing 20 % albumin to crystalloid failed to demonstrate any difference in outcomes including renal function, but proved that albumin itself was safe [37]. The most recent trial in patients with sepsis showed improved survival and a better negative fluid balance in patients with septic shock [38]. Importantly, to-date no negative effect on renal function have been reported from RCTs using 20 % albumin.

Dopamine when used at so-called ‘renal doses’ is still widely used but is ineffective in improving renal function although an increased diuresis on the first day of use has been observed [42]. Indeed, dopamine may worsen renal perfusion in patients with acute kidney injury as determined by change in observed renal resistive indexes [43]. Despite showing promising results in pilot studies on patients at risk of contrast nephropathy [44, 45] and sepsis-associated acute kidney injury [46, 47], selective dopamine A₁ agonists such as fenoldopam have failed to demonstrate significant renal protection in larger studies of either early presumed acute tubular necrosis [48, 49] or contrast nephropathy [50].

Prostaglandins have been investigated mainly in the setting of contrast nephropathy. Both prostaglandin E1 (PGE1) and PGI (Iloprost) administered intravenously resulted in attenuated rise of serum creatinine after the use of contrast media [51, 52]. However, major adverse events include hypotension as well as flushing and nausea at higher doses thereby limiting their extensive use.

Natriuretic peptides improve renal blood flow through afferent glomerular dilatation resulting in an increase in both GFR and urinary sodium excretion and, in addition, B-type natriuretic peptides (BNPs) inhibit aldosterone. Atrial natriuretic peptide (ANP) use in human studies has been controversial attenuating rise in serum creatinine in ischemic renal failure [53] or in AKI after liver transplantation but it is ineffective in large RCTs of both non-oliguric [54] and oliguric AKI [55]. A recent study using low-dose BNP (nesiritide) suggested there was some preservation of renal function in patients with chronic kidney disease stage 3 undergoing cardiopulmonary bypass surgery [56].

Currently, the most promising preliminary reports in the intensive care setting do exist for the adenosine antagonist theophylline for either contrast nephropathy [57–59] as well as some types of nephrotoxic AKI like cisplatin associated renal dysfunction [60]. A randomized placebo controlled trial in neonates with perinatal asphyxia showed significant increase in creatinine clearance after a single dose of theophylline within the first hour of birth [61].

N-acetylcysteine, has been investigated in multiple trials particularly in the setting of contrast nephropathy. Despite several reports showing prevention of contrast nephropathy [66, 67] evaluation of this substance by meta–analyses yields controversial results [68]. Furthermore NAC was ineffective in other circumstances where AKI is common such as major cardiovascular surgery or sepsis [69, 70–72].

Finally studies of IV NAC in both human volunteers as well as patients receiving contrast media demonstrate a decrease in serum creatinine not reflected by concomitant changes of cystatin C considered the more sensitive marker of early changes in GFR [73, 74].

Mannitol, an osmotic diuretic with potential oxygen radical scavenging properties was investigated in randomized trials for the prevention of contrast nephropathy but generally was inferior to general measures such as volume expansion [75]. Some authors favour mannitol for treatment of AKI following crush injuries but controlled trials are still awaited [76].

Selenium is an essential component of the selenoenzymes including glutathione peroxidase and thioredoxin reductase. Selenium supplementation reduces oxidative stress, nuclear factor-B translocation, and cytokine formation as well as attenuating tissue damage. Angstwurm et al. performed a small RCT in 42 patients and showed that selenium supplementation decreased the requirement for RRT from 43 to 14 % [77]. This finding was not reproduced in a consequent prospective RCT in septic shock although selenium appeared to reduce 28 days mortality [78].

Cocktails of antioxidants have been investigated in several small studies showing controversial results. In one randomized trial in patients undergoing elective aortic aneurysm repair use of an antioxidant cocktail resulted in an increased creatinine clearance on the second postoperative day but the incidence of renal failure was very low [79].

Ascorbic acid used in preclinical at high-doses can prevent or restore ROS-induced microcirculatory flow impairment, prevent or restore vascular responsiveness to vasoconstrictors and potentially preserve the endothelial barrier [80]. When given PO 2 h pre-contrast in a single centre trial there appeared to be protection against the development of contrast nephropathy but the rate of AKI in the control group was high and no patients required renal support [81]. A recent meta-analysis on this subject found a renal protective effect of ascorbic acid against contrast-induced AKI [82]. To-date no multicentre randomised control trials have demonstrated any benefit in reducing the rate of AKI by using antioxidant supplementation.