Preventing Acute Renal Failure

Kai Singbartl, MD
University of Pittsburgh,
School of Medicine
Pittsburgh, Pennsylvania, USA

John A. Kellum, MD, FCCM
University of Pittsburgh,
School of Medicine
Pittsburgh, Pennsylvania, USA

References

Acute renal failure (ARF) is defined as a sudden and sustained decline in renal function, resulting in the failure of the kidney to excrete nitrogenous waste products and to maintain fluids and electrolyte homeostasis.1 In critically ill patients, ARF usually occurs in association with multiple organ dysfunction and carries a much higher mortality rate than that seen outside the intensive care unit (ICU). A recent large multi-center observational study of 29,269 critically ill patients found that 5.7% had severe ARF during their ICU stay.2 Of these, 72.5% were treated with renal replacement therapy (RRT). The most frequently seen contributing factor for ARF in the ICU was sepsis (47.5%), and the overall hospital mortality rate was 60.3%.

Non-Pharmacologic Strategies
Non-pharmacologic strategies to prevent ARF include ensuring adequate hydration and circulating blood volume, maintaining adequate perfusion pressure, and minimizing exposure to nephrotoxins. Hydration and Volume Repletion No randomized controlled trials have been performed to assess the role of fluid hydration versus placebo in the prevention of ARF. However, some randomized controlled trials have compared different fluids and have combined fluid hydration with other interventions.3,4 Comparisons of outcome data from these trials to those data from historical, untreated controls suggest a great benefit from fluids.

The type of intravenous (IV) fluids used also may be important. When compared with 0.45% saline in dextrose in a large randomized controlled trial, prophylactic administration of 0.9% saline significantly reduced radio-contrast nephropathy (RCN) in patients undergoing coronary angiography.5 Additionally, a small single-center randomized controlled trial found that prophylactic infusions of isotonic sodium bicarbonate reduced the incidence of RCN compared to infusions of isotonic saline.6 As with many other studies in this area, lack of sufficient power and strong primary outcome parameters limits the clinical relevance of these findings. However, fluid administration should be considered low risk in most patients. As a result, the use of isotonic IV fluids for prevention of RCN is recommended. The composition of such a fluid and the optimal rate of infusion remain unknown. Importantly, just as fluids may be beneficial in preventing of RCN, volume depletion is an important risk.

Maintaining Renal Perfusion Pressure
The two most critical threats to renal perfusion pressure are systemic arterial hypotension and increased intra-abdominal pressure (i.e., intra-abdominal compartment syndrome). While specific recommendations cannot be given because of lack of evidence, one can apply these general guidelines:

• Vasopressor medications (e.g., norepinephrine) should be used only to correct arterial hypotension after, or in conjunction with, intravascular fluid resuscitation.

• There is no evidence to suggest that norepinephrine is associated with increased risk of ARF when used to treat arterial hypotension, and it may be more effective compared to other agents (e.g., dopamine).

• Specific arterial pressure targets for titration of therapy to avoid renal hypoperfusion are not known.  It is common to target a mean arterial pressure of 60 to 65 mm Hg. However, pre-existing comorbidities should be taken into consideration when setting target pressures. 

• Intra-abdominal hypertension is associated with decreased renal perfusion and may result in ARF. Prompt recognition and surgical treatment offer the best potential for recovery.7

Nephrotoxin Exposure
Limiting exposure to nephrotoxins is critical in the prevention of ARF. Aminoglycosides, amphotericin and radiocontrast agents are the most commonly encountered nephrotoxins in the ICU. Aminoglycoside nephrotoxicity develops in approximately 10% to 15% of patients treated with aminoglycosides. Since aminoglycosides are excreted entirely by glomerular filtration, dosing of these drugs seems to be crucial in the development of ARF. Two meta-analyses and one systematic review have evaluated the efficacy and toxicity of multiple-daily and once-daily aminoglycoside dosing schedules.8-10 The studies demonstrated no differences in the efficacy of aminoglycosides when dosed once daily, but they have revealed a trend toward lower nephrotoxicity in the oncedaily dosing groups. Risk of developing ARF during treatment with amphotericin B approaches 30%. The risk for ARF increases with the cumulative dose.11 Whereas standard and lipid formulations of amphotericin B are equally effective, lipid formulations seem to cause less nephrotoxicity.12-14 Lipid formulations are preferred in patients with renal insufficiency or evidence of renal tubular dysfunction. Type, route and volume of contrast media are important risk factors for the development RCN.15 There is a direct correlation between the osmolality of the radiocontrast agent and nephrotoxicity.16 For patients at high risk for RCN, the lowest amount of contrast agent possible is recommended. The agent should be nonionic and iso-osmolar.

Pharmacologic Strategies
So far, most pharmacologic strategies have been predicated on the notion that renal blood flow should be increased or renal oxygen consumption should be decreased. Diuretics Non-oliguric renal failure has been shown to have a better prognosis than oliguric renal failure, and tubular obstruction has been implied in oliguria accompanying acute tubular necrosis, making maintenance of urine flow by means of diuretics an attractive concept. However, a systematic review comparing fluids alone with diuretics in people at risk for ARF found no benefit from diuretics with regard to incidence of ARF, need for dialysis or mortality.17 Moreover, a cohort study showed that diuretic use was associated with a significantly increased risk of death or failure to recover renal function.18 Although a more recent multinational, multi-center observational study found that diuretic use was not associated significantly with increased mortality, there was no evidence of its benefit either.19 One may conclude that there is no evidence to support the use of loop diuretics in the prevention of ARF.

Mannitol
When administered intravenously, mannitol acts not only as an osmotic diuretic but also as a scavenger of free radicals.20 Nonetheless, several small clinical trials evaluating mannitol for the prevention of ARF have not produced clear results.3, 21-23 No adequately powered prospective, randomized clinical trials have compared mannitol with saline alone. While we acknowledge its common use, we cannot recommend mannitol to prevent or treat ARF of any cause.

Dopamine and Fenoldopam
Dopamine increases the glomerular filtration rate (GFR) by vasodilation via dopaminergic receptors, by increasing the cardiac output through ß-adrenergic stimulation, or by increasing perfusion pressure via α-stimulation. Systematic reviews have evaluated the role of dopamine in preventing deterioration of renal function in the ICU.21,24,25 All three concluded that dopamine did not prevent the onset of ARF or the need for dialysis, nor did it decrease mortality rates. The selective dopamine-1 receptor agonist fenoldopam has been shown to improve renal perfusion and  decrease serum creatinine.26,27 However, it failed to decrease the occurrence of ARF in critically ill patients28 or to prevent RCN in patients with chronic renal insufficiency.29 A recent single-center study using a longer duration of fenoldopam in critically ill patients showed a reduction in ARF, defined by an increase in serum creatinine to >1.7 mg/dL, and a trend toward improved survival.30 Additional studies are needed, but the use of fenoldopam appears unlikely in the prevention of ARF, at least as a vasodilator. Moreover, fenoldopam could potentially worsen renal injury by causing hypotension.

Natriuretic Peptides
Members of the atrial peptide family possess natriuretic, diuretic and smooth-muscle relaxant activity through both hemodynamic and tubular mechanisms.31 Four randomized controlled trials have evaluated atrial natriuretic peptide (ANP) in the prevention of ARF and failed to show any benefit.32-35 Interestingly, a small, single-center randomized controlled trial studied postsurgery cardiac patients using a continuous infusion of low-dose human recombinant natriuretic peptide, anaritide.36 This recent trial, unlike larger studies done previously, revealed a decreased need for dialysis, as well as improved survival rates in treated patients who did not undergo dialysis, compared to placebo. Nonetheless, without clear data from large randomized controlled trials, anaritide should not be used to prevent ARF in the general ICU setting. B-type natriuretic peptide (BNP) has similar but more potent effects compared to ANP. Although recent evidence argues against BNP as a cause of ARF, no convincing evidence has emerged as to its likely benefit in prevention or treatment.

Adenosine Antagonists (Theophylline)
In contrast to its systemic effect as a vasodilator, adenosine causes renal arterial vasoconstriction. Several small clinical studies have produced conflicting results regarding the role of theophylline, an adenosine antagonist, in the prevention of RCN.37-40 A recent meta-analysis showed that pretreatment with theophylline led to a smaller increase in serum creatinine compared to placebo.41 This meta-analysis included studies that lacked appropriate controls and limited the outcome to changes in serum creatinine. It is unlikely that theophylline can prevent RCN.

N-Acetylcysteine
Several small studies have demonstrated that N-acetylcysteine (NAC) decreases the incidence of RCN, defined as a 25% increase in serum creatinine after radiocontrast administration.42-45 Several meta-analyses have pooled the existing data and consistently found that NAC, along with fluids, decreases the incidence of RCN compared to fluids alone,46-50 but there was a significant heterogeneity in NAC effect across all the studies. Also, NAC has been shown to decrease serum creatinine without affecting GFR.51 The current implications to reduce serum creatinine after contrast administration with the use of NAC remain unclear and require further exploration. Because of its excellent pharmacoeconomic profile and lack of major toxicity, it still appears reasonable to use NAC together with fluids in high-risk patients to prevent RCN.

Dialysis for ARF Prevention
Although contrast media can be removed by dialysis, insufficient evidence exists for the routine use of prophylactic dialysis to prevent RCN.

Recommended Strategies
Current evidence suggests that non-pharmacologic strategies may be more effective than drugs in the prevention of ARF. Fluids, maintenance of mean arterial pressure and minimizing nephrotoxin exposure still are the most effective strategies. There is now clear evidence that diuretics, dopamine agonists and natriuretic peptides do not prevent ARF or improve outcomes once ARF occurs. Given the low cost, low toxicity and potential benefit, N-acetylcysteine should be considered together with IV hydration to reduce the incidence of RCN in highrisk patients. Theophylline and natriuretic peptides may have possible benefits in specific patient populations, but larger clinical trials are needed to validate their efficacy. The role of prophylactic dialysis to prevent contrast nephropathy is unproven.