| Abstract|| |
Sepsis is an important cause of morbidity and mortality. Acute Kidney Injury (AKI) often complicates sepsis, leading to greater complexity, higher cost of care and worsening prognosis. Despite the improved understanding of its underlying pathophysiological basis, there have been very few interventions, which have consistently been shown to be of value in the management of sepsis-induced AKI. Measures such as adequate hydration, maintenance of adequate circulating blood volume and mean arterial pressure, and avoidance of nephrotoxins, are still the mainstay of prevention. Loop diuretics, mannitol and "low dose" dopamine have been clearly shown to be of no value in the prevention or treatment of AKI and may, in fact, do harm. Among the remaining pharmacological options, N-acetylcysteine (NAC) may have a role in the prevention of radiocontrast induced AKI.
|How to cite this article:|
Rajapakse S, Wijewickrama ES. Non-dialytic management of sepsis-induced acute kidney injury. Saudi J Kidney Dis Transpl 2009;20:975-83
|How to cite this URL:|
Rajapakse S, Wijewickrama ES. Non-dialytic management of sepsis-induced acute kidney injury. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Jun 3];20:975-83. Available from: http://www.sjkdt.org/text.asp?2009/20/6/975/57249
| Introduction|| |
Deterioration of renal function over a short period is termed acute kidney injury (AKI). AKI has replaced the term acute renal failure, and is defined according the RIFLE criteria.  When AKI occurs in the presence of sepsis, without other clear and established non-sepsis related causes of AKI, it is considered sepsisinduced. AKI affects approximately 35% of intensive care unit (ICU) patients,  and close to 50% of AKI is secondary to sepsis.  Thus, sepsis-induced AKI probably occurs in somewhere between 15 and 20% of all ICU admissions.
The severity of AKI correlates with morbidity and mortality of ICU patients. A recent study has shown a linear relationship between the AKI stage and mortality.  The mortality rate of patients with sepsis-induced AKI is high, at approximately 70%. Thus, sepsis-induced AKI is a significant problem in ICU patients. A clear understanding of its pathophysiology, prevention and treatment is essential for the critical care physician. In this paper, we discuss the aspects of supportive care, prevention and therapies, other than renal replacement therapy, in sepsis-induced AKI.
| Pathophysiology of Sepsis-induced AKI|| |
Our understanding of sepsis-induced AKI has advanced very little in the last 50 years. This is mainly due to lack of histopathologic information, which stems from the risks associated with renal biopsy in humans. We rely on indirect forms of assessment such as urine output, urinary sodium concentration, fractional excretion of sodium and fractional excretion of urea to understand the pathophysiology behind sepsis-induced AKI in humans. Such limitations have been overcome to a certain extent by the recent development of animal models, which has enabled more sophisticated and invasive measurements to be made.
AKI in sepsis and septic shock was traditionally thought to result from renal ischemia secondary to inadequate renal blood flow (RBF). This implies that restoration of RBF should therefore, be the primary means of renal protection in septic patients with the risk of AKI. However, recent studies have shown that renal circulation also participates in the systemic vasodilatation observed during severe sepsis/septic shock. Thus, RBF does not diminish, and the development of septic AKI occurs not in the setting of renal hypo perfusion but in the setting of adequate and even increased renal perfusion. ,, Hence, septic AKI may represent a unique form of AKI, namely hyperemic AKI.
However, it is still possible, that despite the preserved or increased global RBF there could be an internal redistribution of blood flow, favoring the cortex and leading to medullary ischemia. Nonetheless, a recent investigation which used laser Doppler flowmetry revealed that the cortical and medullary blood flow remained unchanged in hyperdynamic septic sheep. 
Toxic and immunologic mechanisms are important in mediating renal injury during sepsis. This is due to the release of a vast array of inflammatory cytokines, arachidonate metabolites, vasoactive substances, thrombogenic agents, and other biologically active mediators. For example, tumor necrosis factor-α (TNF) has been demonstrated to play a major role in the pathogenesis of AKI in Gram-negative septic shock. , TNF along with lipopolysaccharides mediates its effect through an increase in pro-apoptotic proteins and a decrease in anti-apoptotic proteins leading to apoptotic cell death of glomerular endothelial cells and proximal tubular cells. ,
Therefore, it is clear that, as evidence accumulates, the paradigms currently used to explain AKI in sepsis is shifting from vasoconstriction and ischemia to vasodilatation and hyperemia and from acute tubular necrosis to acute tubular apoptosis. Hence, our therapeutic approaches need to be altered accordingly.
Given the apparent effect of AKI on mortality, it is important to prevent the occurrence or, hasten the recovery of even the mildest forms of AKI. Management of established AKI includes identification and removal of precipitating factors, treatment of complications such as hyperkalemia, pulmonary edema, acidosis and timely initiation of renal replacement therapy. These management strategies can be broadly divided into non-pharmacologic, pharmacologic and dialytic strategies.
| Non-pharmacologic Strategies for Prevention and Management of AKI|| |
Strategies worth reviewing include hydration and volume loading, maintenance of mean arterial pressure and avoidance of non-ionic contrast agents and nephrotoxic antibiotics.
Hydration and Volume Loading
Although no randomized controlled trials (RCTs) have been carried out, it has long been recognized that intravascular volume depletion is an important risk factor for development of AKI and its correction with fluids leads to resolution of AKI. In certain settings, such as rhabdomyolysis, early and aggressive fluid resuscitation has clearly been shown to be beneficial.  The route of fluid administration may make a difference in terms of outcome. Intravenous 0.9% saline hydration (1 mL/kg/hr for 24 hours) begun 12 hours before catheterization was shown to be superior to unrestricted oral fluid intake in patients undergoing cardiac catheterization.  Recent evidence also suggests that isotonic fluids are preferable to hypotonic fluid resuscitation in the prevention of AKI. A RCT of 1,620 patients comparing isotonic 0.9% saline with a combination of 0.45% saline and 5% dextrose found that infusion with 0.9% saline significantly reduced contrast nephropathy (0.7% vs 2%; P = .04). 
Maintaining Renal Perfusion Pressure
Specific recommendations to maintain renal perfusion are based on expert opinion rather than on good clinical evidence. No absolute number is considered adequate with regard to mean arterial pressure, and target mean arterial pressure should be individualized based on the patient's baseline physiology. Vasopressors should be used to improve perfusion pressure, but only after adequate volume repletion is accomplished. Contrary to previous belief, vasopressors can be used safely for this purpose without any additional risk of developing AKI.  Raised intra-abdominal pressure is associated with decreased renal perfusion. Therefore, its prompt recognition and early surgical treatment offers the best potential for renal recovery. 
Drug Induced Nephrotoxicity
Many patients with sepsis are critically ill often necessitating the use of multiple therapeutic agents, many of which may, individually or in combination, have the potential to cause kidney injury. Several recent studies have shown that nephrotoxic drugs were contributing factors in 19 to 25% of cases of severe acute renal failure in critically ill patients. , Drugs with direct nephrotoxic effects may induce renal injury by several mechanisms [Table 1].
Drug-induced Acute Tubular Necrosis
Aminoglycosides: Aminoglycosides are common causes of drug-induced AKI. Sustained elevations of drug levels that occur from multiple daily doses seem to correlate with toxicity. Repeated studies have shown that nephrotoxicity of aminoglycosides can be minimized by once daily dosing compared to multiple daily dosing without any effect on efficacy. ,, The uptake of aminoglycosides in the proximal tubule is saturable; therefore, the administration of large doses may not result in increased renal uptake. The overall uptake is reduced because the drug is given less often, thus explaining the reduced nephrotoxicity with single daily dosing. The preserved efficacy is explained by two pharmacodynamic properties of aminoglycosides: a) the bactericidal mechanism of action is concentration dependent; and b) prolonged post-antibiotic effect.
Vanocomycin: Vancomycin hydrochloride, which is increasingly being used in the treatment of septic patients with methicillin-resistant Staphylococcus aureus, is associated with nephrotoxicity. The reported frequency ranges from 6 to 30%.  Trough levels > 15 μg/mL are associated with increased risk of nephrotoxicity and peak levels also have been associated with increased nephrotoxicity. The dosing of vancomycin requires careful consideration of renal function and trough levels should be monitored frequently in patients with fluctuating renal function.
Amphotericin B: Amphotericin B associated nephrotoxicity occurs in 25-30% of patients, with progressive increase in the risk of AKI with increase in cumulative dose.  The risk of renal dysfunction is relatively low at doses of < 0.5 mg/kg/day and a cumulative dose of < 600 mg. The use of lipid formulations of amphotericin B seems to cause less nephrotoxicity compared with standard formulations. , Therefore, lipid forms of amphotericin B should be used preferentially in patients with renal insufficiency or evidence or renal tubular dysfunction.
Drug-Induced Acute Interstitial Nephritis
Many drugs, which are commonly used in the critical care setting, are associated with acute interstitial nephritis (AIN) [Table 2], and account for 3 to 15% of all drug-induced acute renal failure.  Renal dysfunction usually occurs 7-14 days after exposure and when it occurs secondary to β-lactam antibiotics and sulfa drugs, may be associated with fever, eosinophilia and rash. Renal manifestations include sterile pyuria, eosinophiluria, and an inflammatory infiltrate in renal interstitium on histology. Reactions are generally idiosyncratic, and management involves removal of the suspected causative agent and supportive therapy. Several case series suggest that treatment of biopsy-proven AIN with prednisolone 1 mg/ kg/day for up to four weeks may accelerate the rate of recovery. ,
Iodinated contrast media are commonly used during the diagnostic workup of critically ill patients. AKI is a well recognized complication of contrast media resulting in increased in-hospital mortality, prolonged hospital stay and increased health care costs , The most important risk marker for developing AKI following contrast administration is the baseline glomerular filtration rate (GFR), with increased risk of AKI below estimated GFR of 60 mL/ min. Other risk factors include diabetes mellitus, heart failure, volume depletion, nephrotoxic drugs, hemodynamic instability and the presence of other co-morbidities.
The type and volume of contrast media administered influence the risk of contrast nephropathy in critically ill patients. In general, higher the osmolality of contrast media, greater is the risk of nephrotoxicity. Recent studies have shown that the use of iso-osmolar (approximately 290 mOsm/kg) contrast media is associated with considerably lesser nephrotoxicity compared to the use of low (500-800 mOsm/ kg) and high osmolar contrast media. , Numerous studies have shown that the volume of the contrast medium is a risk factor for development of contrast nephrotoxicity. ,, Theonly measure that has been shown to be beneficial in preventing contrast-induced AKI is volume expansion prior to the procedure, preferably with intravenous isotonic fluids.
Although popular, N-acetylcysteine (NAC) has not consistently been shown to be effective. A recent review of nine published meta-analyses on the value of NAC in preventing contrast nephrotoxicity revealed that there was significant heterogeneity in the benefit of NAC across studies.  Moreover, the dose-dependent reduction in serum creatinine after contrast administration with the use of NAC in these studies, have to be interpreted in the light that NAC has been shown to decrease serum creatinine without improving the GFR,  possibly by activating creatinine kinase activity and/or by increasing tubular secretion. Hence, the value of NAC in preventing contrast nephrotoxicity is unclear and needs to be further explored. However, given its low cost and excellent side effect profile, it would seem prudent to use NAC along with intravenous fluids in all highrisk patients who are receiving intravenous radiocontrast.
Other pharmacologic agents tested in small trials that deserve further evaluation include theophylline, statins, ascorbic acid, and prostaglandin E1. Fenoldapam, dopamine, calcium channel blockers, atrial natriuretic peptide, and L-arginine have not been shown to be effective in the prevention of contrast induced AKI. Furosemide, mannitol, and an endothelin receptor antagonist are potentially detrimental. 
Although contrast media can be removed by dialysis, there is no clinical evidence that prophylactic dialysis reduces the risk of AKI, even when carried out within one hour or simultaneously with contrast administration. However, hemofiltration performed before and after contrast deserves further investigation, given reports of reduced mortality and need for hemodialysis following its use in ICU patients.  Nonetheless, the high cost and need for prolonged ICU care will limit the utility of this prophylactic approach.
| The Role of Loop Diuretics|| |
Loop diuretics reduce the energy requirement of the cells of the thick ascending limb of loop of Henle by inhibiting the Na + /K + /Cl - pump in the luminal cell membrane and can theoretically reduce renal tubular oxygen demand.  In vitro studies of peripheral mononuclear cells stimulated with lipopolysaccharide have shown that high concentrations of frusemide lead to reduced expression of TNF, interleukin-6 and interleukin-8.  Thus, at least theoretically, the timely administration of frusemide might attenuate or reduce the severity of kidney injury.
The presence of oliguria, in the context of AKI, is associated with increased mortality compared to non-oliguric AKI. , The risk of volume overload is less, maintenance of potassium and acid-base homeostasis is easier and dialysis requirements are reduced with nonoliguric AKI. Most clinicians therefore use high doses of loop diuretics to convert oliguric AKI to non-oliguric AKI. In a multicenter observational study involving 552 ICU patients with AKI, 59% received diuretic therapy before consultation with a nephrologist.  In another large, multicenter, multinational, observational study of 1,700 patients with AKI, 70% received diuretics at the time of study enrollment. 
However, repeated studies have failed to demonstrate any significant benefit of using loop diuretics in AKI. A prospective observational study was performed by Mehta et al, at five academic hospitals from 1989 to 1995. They enrolled 552 ICU patients with AKI, and their findings suggested an increased risk of death and/or non-recovery of kidney function with the use of loop diuretics.  These findings were similar to the prospective observational study done by Uchino et al, who enrolled 1,743 ICU patients with AKI from 54 ICUs in 23 countries.  Two systematic reviews and a meta-analysis, which were carried out recently, further confirmed the above findings, showing that there is no benefit of loop diuretics on improving survival or renal recovery following AKI. ,,
| The Role of Osmotic Diuretics - Mannitol|| |
Animal models have shown that mannitol is effective in attenuating the reduction in GFR associated with experimental ATN, when administered before the ischemic insult and the offending nephrotoxin.  In addition, mannitol has also been shown to increase renal blood flow and to act as a free radical scavenger during reperfusion of the kidney. However, in clinical practice the role of mannitol is less well established. Use of mannitol in patients with mild to moderate renal insufficiency was shown to be associated with greater risk of renal injury when compared to hydration with saline alone.  In a retrospective analysis of 24 patients admitted to ICU with rhabdomyolysis, use of mannitol was not associated with improved outcome when compared to aggressive hydration alone.  Thus, the use of mannitol cannot be scientifically justified in the prevention or management of AKI.
| Vasoactive Drugs|| |
Sepsis is often associated with systemic vasodilatation causing a decrease in systemic arterial pressure despite a normal or even increased cardiac output. Under these circumstances, hypotension may persist despite vigorous volume expansion. Potent systemic vasopressor agents such as high-dose dopamine, epinephrine, phenylephrine, or low-dose vasopressin or terlipressin can be used to restore an acceptable mean arterial blood pressure. When septic shock is complicated with AKI, the use of vasopressors is typically fraught with controversy because of the belief that renal vasoconstriction is responsible for AKI and that such drugs will make renal vasoconstriction worse and induce more kidney injury.
However, recent studies have clearly shown that these concerns are unfounded and that in these patients, vasopressor therapy is safe and probably beneficial from a renal point of view. Norepinephrine is currently considered the vasopressor agent of choice in the management of septic shock. Contrary to the previously held belief that norepinephrine may decrease vital organ blood flow, including renal blood flow, due to its a-adrenergic effects, recent studies have clearly shown that renal perfusion improves significantly with norepinephrine in patients with septic shock.  This is considered partly due to the rise in mean arterial pressure and partly due to the renal vasodilatation caused by decreased renal sympathetic tone through baroreceptor stimulation by increase in systemic blood pressure.  Norepinephrine was found superior to high-dose dopamine in the management of septic shock in a recent study by Martin and colleagues.  These investigators randomized 32 patients with septic shock to either receive high-dose dopamine (up to 50 μg/kg/min) or norepinephrine (up to 1 μg/kg/ min) to achieve a predetermined arterial blood pressure of 80 mmHg. They found that highdose dopamine failed to restore the target blood pressure in one third of patients while norepinephrine succeeded in all patients. Urinary output was significantly and markedly improved from baseline once blood pressure was increased. The same investigators reported the outcome of 97 adult patients with septic shock, where the patients who were treated with norepinephrine had a lower mortality compared to those treated with other vasopressor agents.  These findings support the argument that norepinephrine is safe and effective in septic shock, and that its renal effects under such circumstances are likely to be beneficial.
There are no controlled studies to directly compare the other vasopressor drugs with norepinephrine. However, phenylephrine and adrenaline are not recommended as first line agents because of concern regarding unbalanced vasoconstriction with phenylephrine and lack of sufficient human data, and in the case of adrenaline, concern about its greater tendency to induce hyperlactemia, acidosis, hyperglycemia and tachycardia. On the other hand, lowdose vasopressin (10 IU/hr), when used in combination with norepinephrine, allowed decreasing the dose of norepinephrine in the treatment of septic shock without demonstrating any other added benefit. 
| Low-dose Dopamine|| |
Dopamine is a catecholamine with dose dependent effects on the systemic and renal vasculature. In healthy subjects, low-dose dopamine (0.5 to 3 μg/kg/min) increases renal blood flow and promotes natriuresis through stimu-lation of renal D1, D2 and D4 receptors and thus, may protect the kidney from acute tubular necrosis.  It is commonly used in the treatment of renal dysfunction and oliguria in the critically ill. ,
However, despite its popularity, repeated studies have failed to demonstrate a significant benefit of its use in the prevention or treatment of AKI. A recent meta-analysis, which identified 61 randomized and quasi-randomized controlled trials enrolling 3359 patients, revealed that there was no significant benefit in the use of low-dose dopamine, in reducing death or need for renal replacement therapy.  The novel finding of this review was that low-dose dopamine increased urine output by 24% (CI, 14% to 35%) on the first day of therapy, with the effect decreasing and not statistically significant thereafter. The early diuretic effect and apparent safety of low-dose dopamine may explain its continued popularity.
| Role of Insulin and Tight Glycemic Control|| |
The use of aggressive insulin therapy aimed at achieving euglycemia in critically ill patients has been shown to reduce the development of severe acute renal failure that required renal replacement therapy (8.2% versus 4.8%; P = 0.04).  A possible explanation for this finding may relate to the fact that insulin may play an important anti-inflammatory role in sepsis. Insulin also has a powerful anti-apoptotic effect, which is beneficial in preventing oxidative stress-mediated tubular epithelial cell damage, induced by high glucose concentration. A very large, multicenter, randomized, controlled study to assess the effectiveness of intensive insulin therapy in critically ill patients is underway,  and will likely further increase our understanding of whether tight glucose control does indeed benefit the kidney in critical illness and sepsis.
| Conclusions|| |
AKI occurs commonly in critically ill patients. Even modest derangements in renal function significantly worsen mortality and add to morbidity. Thus, considerable effort has been expended to develop techniques to prevent AKI or to facilitate its resolution. Despite the improved understanding of its pathophysiological basis, only few preventive and therapeutic strategies have been shown to be of value in the management of sepsis-induced AKI. Strategies such as avoidance of hypotension and dehydration and minimizing exposure to nephrotoxins continue to be the mainstay of minimizing AKI in the critical care setting. Use of "low-dose" dopamine, loop diuretics and mannitol has no place in the prevention or treatment of AKI. Given its low cost and excellent side effect profile, it would seem prudent to provide NAC along with intravenous fluids to all high-risk patients who are receiving intravenous radiocontrast. Further well powered randomized studies need to be carried out to improve preventive and treatment strategies in the management of sepsis-induced AKI.
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Department of Clinical Medicine, Faculty of Medicine, University of Colombo
[Table 1], [Table 2]