Prevention and Treatment of Acute Renal Failure in Sepsis

Acute renal failure (ARF) is a common complication of sepsis and carries an ominous prognosis. Mortality was reported higher in patients with septic ARF (74.5%) than in those whose renal failure did not result from sepsis (45.2%) (1). Although the presence of multiple organ dysfunction and other comorbidities certainly contributes to the high mortality, ARF independently increases morbidity and mortality (2). Sepsis is characterized by a generalized inflammatory response and activation of the coagulation and fibrinolytic cascades, resulting in endothelial injury (2a,2b). A broad array of humoral mediators are released in the systemic circulation, including cytokines, lipid mediators such as platelet activating factor and arachidonic acid metabolites, endothelin-1, and complement components. Systemic hypotension, resulting in renal ischemia, is a contributing — but certainly not the sole — factor in septic ARF. Intrarenal vasoconstriction, owing to an imbalance between vasodilatory and vasoconstrictory substances, results in a decline in renal blood flow (RBF) and abnormalities in intrarenal blood flow distribution that predominantly affect the outer medulla (3). Inflammatory cells infiltrate the kidney, causing local damage by release of oxygen radicals, proteases, and further production of inflammatory cytokines. Leukocyte-endothelial interactions result in physical congestion of the medullary vasculature and a further decreased regional blood flow. Dysfunction of the coagulation and fibrinolytic cascades contributes to intraglomerular thrombosis. Tubular injury leads to cell detachment with intratubular obstruction and tubular backleak. Recovery from ARF requires clearance of necrotic tubular cells and debris, as well as regeneration and repair of the nonfatally injured cells. The present communication will discuss the attempts to pharmacologically interfere with each of these dysfunctional pathways to improve the course of septic ARF, including inhibition of inflammatory mediators, improvement of renal hemodynamics by amplifying vasodilator mechanisms and blocking vasoconstrictor mechanisms, interruption of leukocyte infiltration, inhibition of the coagulation cascade, and administration of growth factors to accelerate renal recovery. Furthermore, the available supportive measures including dialytic treatment will be highlighted. Treatment with Fluids, Vasopressors, and Diuretics Few studies addressed the issue of treatment with fluids, vasopressors, and diuretics specifically in patients with septic ARF. However, conclusions can probably be safely inferred from studies performed in patients with ARF in general, which will be included in the discussion below. Volume Expansion It is common knowledge that optimization of systemic hemodynamics and effective intravascular volume is important to prevent ARF in patients with sepsis. Unfortunately, what constitutes optimal hemodynamics remains largely undefined. In a multicenter randomized trial, volume expansion and vasopressor therapy aimed at achieving supranormal values for cardiac index and normal values for mixed venous oxygen saturation had no effect on mortality or on the incidence and severity of ARF (4). In contrast, early institution of treatment to increase central venous oxygen saturation to 70% or higher resulted in a lower mortality and less severe organ dysfunction in patients with severe sepsis or septic shock (5). Furthermore, the nature of the optimal fluid resuscitation regimen has not been defined. Three systematic reviews of randomized controlled trials comparing crystalloids with colloids have yielded conflicting results (6–8). A meta-analysis of trials comparing administration of albumin with no administration or with administration of crystalloids in critically ill patients found a strong suggestion that albumin increases mortality (6). A meta-analysis of trials comparing colloid with crystalloid solutions reported that resuscitation with colloids was associated with an absolute increase in the risk of mortality of 4% (7). In contrast, another meta-analysis of trials comparing isotonic crystalloids with colloids did not find a difference in mortality (8). Although the controversy over the choice of crystalloids or colloids as the ideal resuscitation fluid persists, a recent randomized trial in 129 patients with severe sepsis or septic shock demonstrated that the use of hydroxyethylstarch as plasma-volume expander was associated with a significantly higher risk of ARF than gelatin (9). In keeping with these findings, the use of hydroxyethylstarch in brain-dead kidney donors was associated with renal dysfunction in the kidney transplant recipients (10). However, a randomized trial of 300 trauma or postoperative patients with sepsis found no difference in mortality or incidence of renal failure between patients resuscitated with hydroxyethylstarch or albumin (11). In conclusion, despite the importance of fluid therapy in the prevention and treatment of ARF, the nature and targets of an optimal fluid resuscitation regimen continue to be an unresolved issue. Vasopressors When appropriate volume expansion fails to restore BP in patients with sepsis, vasopressors are indicated. Physicians have been concerned about their use for fear that intrarenal vasoconstriction would abrogate the benefits of increased BP. Norepinephrine, indeed, reduces RBF in healthy animals and humans (12). The ultimate effect of norepinephrine on renal perfusion depends, however, on a complex interplay of its actions on different vascular beds and the underlying condition of the patient. Norepinephrine increases BP by an α1-mediated increase in systemic vascular resistance and a β1-mediated increase in cardiac output. An excessive rise in systemic vascular resistance with an increase in cardiac afterload may have a potential negative impact on cardiac output. The net effect on renal vascular resistance hinges on (1) the increase in systemic BP with a decreased renal sympathetic tone through a baroreceptor response, resulting in vasodilatation; (2) an autoregulatory vasoconstriction owing to a rise in renal perfusion pressure; (3) a direct α1-mediated renal vasoconstriction, which is of minor importance (12). Thus, in a patient with sepsis, characterized by systemic vasodilatation and impaired renal autoregulation, norepinephrine administration may be expected to improve RBF. Several non-controlled studies in patients with sepsis have, indeed, shown that norepinephrine augmented urine output and GFR (12). The only randomized trial available reported that norepinephrine administration in 32 patients with septic shock resulted in a higher BP, systemic vascular resistance, and diuresis than high-dose dopamine (13). A prospective observational study in 97 patients with septic shock found a lower mortality in patients treated with norepinephrine than in those treated with other vasopressors — mainly high-dose dopamine (14). Vasopressin, a hormone secreted by the posterior pituitary, increases systemic vascular resistance through activation of V1a-receptors on vascular smooth muscle cells. administration in patients with septic shock and to increased BP, systemic vascular resistance, and urine output A randomized trial in patients with septic shock demonstrated that a of urine output and clearance with on BP and cardiac as with norepinephrine In conclusion, vasopressors can be safely to restore BP renal in patients with septic Norepinephrine is to In patients to early use of is dopamine to increases and in healthy animals and humans actions that may be of potential in patients with or at risk of ARF. of dopamine has been in different of ARF, including ARF and or no the of dopamine as a in patients at high risk for ARF negative but to in study patient or a incidence of ARF in the In ARF, or randomized trials no effect or a improvement of or GFR with dopamine In a study of critically ill of and in a clearance dopamine diuresis clearance In a the of patients not treated with dopamine with those treated with or high-dose for severity of the use of dopamine was not associated with a lower risk for or in a randomized trial in critically ill patients with early renal dysfunction to a was no effect of dopamine on renal for or of or mortality Furthermore, is about the potential of at can and and In a of dopamine owing to a of blood from the In dopamine was found to the of for and to cell In conclusion, the use of dopamine for be as is no its in and dopamine can and in critically ill Diuretics diuretics are in critically ill patients with early or ARF. 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