Prevention and Treatment of Acute Renal Failure in Sepsis
Authors: An S. De Vriese
Journal: Journal of the American Society of Nephrology (2003)

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. Arginine vasopressin administration in 16 patients with septic shock and hyporesponsiveness to catecholamines increased BP, systemic vascular resistance, and urine output (15). A randomized trial in 24 patients with septic shock demonstrated that a 4-h infusion of arginine vasopressin improved urine output and creatinine clearance with similar effects on BP and cardiac output, as compared with norepinephrine (16). In conclusion, vasopressors can be used safely to restore BP without compromising renal function in patients with septic shock. Norepinephrine is preferable to dopamine. In patients refractory to norepinephrine, early use of arginine vasopressin is recommended (17). Low-Dose Dopamine Low-dose dopamine (1 to 3 μg/kg per min) increases RBF, diuresis, and natriuresis in healthy experimental animals and humans (18–19), actions that may be of potential benefit in patients with or at risk of ARF. Administration of low-dose dopamine has been examined in different models of experimental ARF, including ischemic ARF and septicemia, demonstrating protective or no beneficial effects (18–19). Studies examining the role of low-dose dopamine as a prophylactic agent in patients at high risk for ARF were generally negative but lacked statistical power due to limitations in study design, small patient numbers, or a low incidence of ARF in the control group (18–19). In established ARF, several uncontrolled case series or small randomized trials showed either no effect or a (usually transient) improvement of diuresis, natriuresis, or perhaps GFR with low-dose dopamine (18–19). In a study of 18 critically ill patients, short-term infusions of low-dose dopamine, low-dose dobutamine, and placebo were compared in a randomized, double-blind, crossover fashion. Dobutamine improved creatinine clearance without affecting diuresis, while dopamine induced diuresis without changing creatinine clearance (20). In a larger study, primarily investigating the value of atrial natriuretic peptide, patients not treated with dopamine were compared with those treated with either low-dose (3 μg/kg per min) or high-dose (>3 μg/kg per min) dopamine. After adjustment for severity of illness, the use of dopamine was not associated with a lower risk for death or dialysis (21). Finally, in a randomized placebo-controlled trial in 328 critically ill patients with early renal dysfunction sufficiently powered to detect a small benefit, there was no effect of low-dose dopamine on renal function, need for dialysis, ICU or hospital length of stay, or mortality (22). Furthermore, there is concern about the potential side effects of dopamine, even at low doses. Dopamine can depress respiratory drive and trigger tachyarrhythmias and myocardial ischemia (18–19). In a porcine model of hemorrhagic shock, dopamine accelerated intestinal ischemia owing to a shunting of blood away from the bowel mucosa (23). In addition, dopamine was found to suppress the circulating concentrations of all anterior pituitary-dependent hormones, except for cortisol (24), and to decrease T cell function (18–19). In conclusion, the use of low-dose dopamine for renoprotective purposes should be abandoned, as there is no evidence supporting its effectiveness in this setting and dopamine can precipitate serious cardiovascular and metabolic complications in critically ill patients. Diuretics High-dose loop diuretics are commonly used in critically ill patients with early or established ARF. The rationale for their use rests heavily on the assumption that they decrease oxygen consumption in the tubular cells by inhibiting transcellular sodium transport and thus prevent or limit ischemic cell injury. In addition, loop diuretics may vasodilatate cortical blood vessels and improve oxygenation. Finally, augmentation of tubular flow may reduce intratubular obstruction and backleak of filtrate, thereby accelerating resolution of ARF. Prophylactic administration of loop diuretics in patients at high risk for ARF contra-intuitively appeared to be deleterious to renal function (25–26). Although no specific information on septicemic patients is available, physicians should be discouraged from using diuretics in these patients in an effort to prevent ARF. In patients with established ARF, several studies have found no benefit of loop diuretics (27–33) (Table 1). More particularly, loop diuretics did not accelerate renal recovery, reduce the need for dialysis, or decrease mortality. Most of these studies were, however, relatively small and lacked statistical power to entirely rule out a beneficial effect of diuretics. Table 1: Studies examining the value of loop diuretics in established ARFLoop diuretics may convert oliguria to diuresis in a subset of patients with ARF. The mortality rate of non-oliguric ARF was found to be lower than that of oliguric ARF (33–34). There were, however, no significant differences in the clinical characteristics, the severity of renal failure, and the mortality rate between spontaneously non-oliguric patients and patients becoming non-oliguric after furosemide (33–34). These observations imply that patients responding to loop diuretics are characterized by a less severe form of renal failure, rather than a beneficial effect of therapy. In a recent retrospective survey of critically ill patients with ARF, diuretic use was associated with an increased risk of death and non-recovery of renal function (35). The authors suggested that the adverse outcome was due to either direct deleterious effects of diuretics or indirect effects owing to a delay in the recognition of the severity of ARF and institution of dialytic support. The higher odds for death or non-recovery of renal function was, however, borne largely by patients who were relatively unresponsive to diuretics (35), suggesting that diuretics were preferentially used in patients with an intrinsically more severe course of disease. In conclusion, despite their ubiquitous use, only few and small studies have evaluated the role of loop diuretics in established ARF. This contrasts sharply with the testing of other pharmacologic agents in critically ill patients where mega-trials are the rule (see below), illustrating to what extent the scientific arena is dominated by the interests of the pharmaceutical industry. In the absence of data from a sufficiently powered multicenter randomized trial, high-dose loop diuretics should be used cautiously in critically ill patients with ARF. Intravascular volume depletion should be carefully corrected before and during administration of diuretics, as an already damaged kidney may be profoundly injured by a relatively mild decrease in perfusion pressure. In patients with sustained oliguria despite high doses of loop diuretics, this treatment should be withdrawn. In responders, continuous infusions are preferred because they are more effective and associated with less toxicity than bolus administrations (36). Specific Pharmacologic Treatment Anti–TNF-α Therapy Rationale. Tumor necrosis factor-α (TNF-α) is a pleiotropic cytokine that plays a germane role in the host response to infection. Besides its well-documented systemic effects, TNF-α may have specific renal effects. Mesangial cells produced TNF-α when exposed to LPS (37). In vivo TNF-α infusion in rabbits (38) or perfusion of the isolated rat kidney with TNF-α (39) decreased GFR. TNF-α caused leukocyte and fibrin accumulation in glomerular capillary lumens (38) and potently induced apoptotic cell death in glomerular endothelial cells (40). Experimental Studies. A large number of studies in diverse animal models have shown that anti-TNF-antibodies confer protection against the morbidity and mortality from both Gram-positive and Gram-negative sepsis (41). Specifically for the kidney, passive immunization to TNF-α prevented renal cortical damage during endotoxemia in rhesus monkeys (42). Neutralization of TNF-α with a TNF-soluble receptor protected mice against LPS-induced renal failure (43). Mice with a targeted deletion of TNF receptor-1 (TNFR1−/−) were resistant to LPS-induced renal failure (44). Kidneys of TNFR1−/− mice had less tubular damage, less neutrophil infiltration, and a lower number of apoptotic cells than those of TNFR1+/+ mice. In addition, TNFR1+/+ kidneys transplanted in TNFR1−/− mice sustained severe renal failure after LPS injection, whereas TNFR1−/− kidneys transplanted in TNFR1+/+ mice were relatively protected. Finally, the fact that TNFR1−/− mice remain sensitive to the lethal effects of LPS (45) but are resistant to LPS-induced renal failure further supports a renal-specific role for TNF-α. Clinical Studies. More than ten large phase III trials with neutralizing monoclonal anti–TNF-α antibodies or soluble TNF receptor fusion proteins failed to show survival benefits in patients with sepsis (41). Preliminary results of a recently completed trial with afelimomab were somewhat more encouraging. The monoclonal anti-TNF-α antibody conferred a 6.9% absolute and 14.3% relative reduction in risk-adjusted mortality in septic patients with interleukin-6 concentrations of more than 1000 pg/ml (46). Although the BAY 1351 monoclonal anti-TNF-α antibody did not improve survival in patients with septic shock, a reduction in the development of renal failure was observed (47). Conclusion. Although TNF-α indirectly affects the kidney by inducing hypotension and releasing inflammatory mediators in the circulation, several lines of evidence point to direct TNF-mediated renal damage in sepsis. Despite the apparent success of anti-TNF therapies in animal models with prevention of both mortality and renal failure, the beneficial effects of these strategies in humans are marginal at best. A more profound knowledge of cytokine profiles in septicemia may allow for a better selection of patients that will most likely benefit from these therapies. Inhibition of Platelet-Activating Factor Rationale. Platelet-activating factor (PAF) is an endogenous phospholipid with vasoactive, platelet-aggregating and pro-inflammatory properties. Serum and urinary concentrations of PAF are elevated in septic patients and correlate with the severity of ARF (48). LPS and TNF-α stimulate the synthesis of PAF in mesangial cells, endothelial cells, and leukocytes. Intrarenal infusion of PAF in the rat results in renal vasoconstriction and a fall in GFR (49–50). Experimental Studies. Several structurally unrelated PAF antagonists prevented the adverse renal hemodynamic effects of endotoxemia in the rat (49–50). Clinical Studies. A large phase III trial with PAF acetylhydrolase, a recombinant form of the endogenous human enzyme that hydrolyzes PAF, has been initiated in patients with severe sepsis (51). Conclusion. Although experimental studies are encouraging, no firm conclusions on the value of PAF antagonism in septic ARF can be drawn in the absence of information from clinical trials. Inhibition of Nitric Oxide Synthase Rationale. Nitric oxide (NO) is the metabolic product of L-arginine and is produced by three major NO synthase (NOS) isoforms that are expressed in a cell-type specific manner and each have a distinct functional role: endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS). Within the kidney, eNOS is constitutively expressed in endothelial cells and plays a pivotal role in vascular relaxation, inhibition of leukocyte adhesion, and platelet aggregation. Sublethal endothelial injury and endothelial dysfunction, resulting in an impaired release of NO produced by eNOS, have been described in ischemic kidneys (52–53). On the other hand, iNOS is located in diverse cell types in the kidney but is normally not active. As regards septicemia, it is of interest that LPS exposure upregulates iNOS in the medulla and glomeruli (54). TNF-α and interleukin-1 induce the expression of iNOS in mesangial cells, vascular smooth muscle cells, and macrophages. Excessive generation of NO by iNOS has been implicated as an important mediator of the hemodynamic alterations in sepsis, particularly the vascular hyporesponsiveness and vasodilatation (55). These alterations in NOS expression and NO production in the systemic circulation and within the kidney have supported the extensive testing of NOS inhibitors in various models of sepsis and renal ischemia. Experimental Studies. N-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor, prevented hypoxic cellular damage in isolated proximal tubules (56), whereas L-arginine enhanced the injury (56–57). NO thus appears to be cytotoxic to renal tubular cells. In contrast to the protective effects in isolated renal tubules, L-NAME resulted in an increase in proteinuria, a decline in renal function and a marked fibrin deposition and glomerular thrombosis during in vivo endotoxemic injury (58). Escherichia coli bacteremia in the rat increased cardiac output and caused renal hypoperfusion due to preglomerular vasoconstriction. In this model, L-NAME normalized cardiac output but exacerbated preglomerular vasoconstriction and further impaired glomerular blood flow (59). During Pseudomonas aeruginosa sepsis in sheep, L omega-mono-methyl-arginine (L-NMMA) increased BP and systemic vascular resistance and decreased cardiac output, whereas RBF remained unchanged (60). N-methyl-L-arginine (L-NMA) fully reversed the decrease in BP and partially the decrease in RBF occurring in dogs after LPS infusion (61). These variable and contradictory results with nonselective NOS inhibitors suggest that alternative sources of NO in the systemic circulation and within the kidney exert opposite effects. It was therefore anticipated that the use of selective NOS inhibitors would produce less ambiguous results. Antisense oligodeoxynucleotides targeting iNOS improved renal function in rats subjected to renal ischemia (53). The effect was due to an attenuation of tubular injury, suggesting cytotoxic effects of NO produced by iNOS during renal ischemia. Similarly, the selective iNOS inhibitor L-N6-(1-iminoethyl)lysine (L-NIL) conferred renoprotective effects during ischemia (62). Selective iNOS inhibition with S-methyl-isothiourea prevented hypotension through systemic vasoconstriction and maintained cardiac output and reduced the signs of renal dysfunction in rats challenged with LPS (63). In a hyperdynamic porcine model of sepsis, both L-NAME and S-methyl-isothiourea increased BP and caused comparable reductions of medullary and cortical blood flow (64). Only L-NAME was clearly detrimental to renal function by reducing GFR and increasing sodium excretion and renal oxygen extraction. S-methyl-isothiourea did not affect GFR and reduced sodium excretion. However, apart from increasing MAP, this selective inhibitor of iNOS offered little advantage to the kidneys as compared with saline resuscitation (64). In agreement, the degree of renal failure after LPS infusion was similar in iNOS knockout mice as compared with wild-type mice (43). Clinical Studies. Several small and uncontrolled studies demonstrated that short-term nonselective NOS inhibition increased both BP and systemic vascular resistance and decreased cardiac output in patients with septic shock (65–67). Beneficial effects on renal function were, however, not reported. A randomized, placebo-controlled trial with L-NMMA was discontinued early because of an increased mortality in the treated group. Conclusion. The ubiquitous nature and the pleiotropic effects of the NO system, as well as its complex alterations in sepsis and ARF, likely explain why NOS inhibition fails to show straightforward laudable effects. NO release by the endothelial cells of the renal microcirculation is essential to counterbalance the vasoconstrictor influences and maintain RBF, to inhibit infiltration of leukocytes, and to prevent thrombosis. In contrast, excessive NO production in tubular cells exacerbates the injurious effects of ischemia on these cells. In addition, exaggerated NO-mediated systemic vasodilatation is deleterious for the kidney by reducing perfusion pressure. Future therapies that inhibit iNOS but amplify eNOS may prove to be beneficial. Endothelin Antagonism Rationale. Endothelin-1 (ET-1) is a peptide with potent vasoconstrictor effects on the renal microcirculation, thereby reducing RBF and GFR. Its effects are mediated by at least two types of receptors, the ETA and ETB receptors. Infusion of endotoxin greatly increases plasma ET-1 levels in experimental animals. TNF-α stimulates the synthesis of ET-1 in glomerular endothelial and epithelial cells. In humans with sepsis, plasma ET-1 levels are markedly elevated and correlate with morbidity and mortality (68). Experimental Studies. Pretreatment with a nonselective ET receptor-antagonist, blocking both ETA and ETB receptors, did not improve hypotension but increased RBF, creatinine clearance, and diuresis in canine endotoxemia (69). Similarly, the nonselective ET receptor-antagonist tezosentan induced a significant fall in BP but prevented the reduction in RBF and GFR during endotoxic shock in neonatal piglets (70). Furthermore, an anti-ET-1 antibody improved renal function after endotoxin injection in rats (71). In contrast, renal hemodynamics were unaffected by a nonselective ET receptor-antagonist in porcine endotoxic shock (72), as well as by a selective ETA receptor-antagonist in conscious rats subjected to LPS infusion (73). Clinical Studies. No studies with ET receptor-antagonists have been performed in patients with sepsis. A nonselective ET antagonist increased the risk of contrast nephropathy in patients with chronic renal failure undergoing coronary angiography. These negative effects were thought to relate to an intrarenal “steal” phenomenon, due to an predominant increase of the cortical blood flow with a worsening of medullary ischemia (74). Conclusion. The mixed results in experimental models of sepsis and the deleterious effects in human contrast nephropathy dictate the need to reexamine the rationale for ET antagonism before embarking on clinical trials in patients with ARF and sepsis. Inhibitors of Arachidonic Acid Metabolism Rationale. Metabolism of arachidonic acid by cyclooxygenase results in the generation of prostaglandins and thromboxanes, whereas lipoxygenase yields leukotrienes. Both prostaglandin E2 and I2 (prostacyclin) induce renal vasodilatation and natriuresis, whereas thromboxane A2, leukotrienes, and stable keto-analogues of the endoperoxides prostaglandin F2 and prostaglandin H2 are potent renal vasoconstrictors. Spontaneous oxidation of arachidonic acid by oxygen-free radicals generates prostaglandin F2-like compounds. One of these compounds, 8-epi-prostaglandin F2α has an extremely potent selective renal vasoconstrictive effect through interaction with the thromboxane receptor (75). Endotoxin as well as various inflammatory cytokines stimulate the synthesis of thromboxane A2 and leukotrienes in the kidney and in inflammatory cells (75). The urinary excretion of thromboxane A2 and prostacyclin metabolites are increased several-fold in patients with sepsis (76). Experimental Studies. Cyclooxygenase inhibition with indomethacin had a markedly protective effect on glomerular hemodynamics in endotoxemic rats (77). A selective thromboxane synthetase inhibitor attenuated the renal effects of LPS in the rat (78) and protected the kidney in sheep with hyperdynamic septic shock (79). Furthermore, leukotriene antagonism had beneficial effects on renal function in experimental endotoxemia in rats and dogs (75). Clinical Studies. In patients with sepsis, cyclooxygenase inhibition with ibuprofen reduced the synthesis of thromboxane and prostacyclin, but it had no effect on the development of shock or renal failure and did not improve survival (76). Clinical studies with selective thromboxane or leukotriene inhibitors have not been performed. Conclusion. Cyclooxygenase inhibition is expected to decrease both vasodilatory and vasoconstrictive derivatives of arachidonic acid metabolism. As vasodilatory prostaglandins may be important to maintain RBF by opposing the vasoconstrictive influences, the failure of ibuprofen to improve renal function in sepsis is not surprising. In the absence of clinical studies with selective thromboxane or leukotriene inhibitors, no meaningful conclusions on their potential benefit can be drawn. Natriuretic Peptides Rationale. Atrial natriuretic peptide (ANP), a hormone synthesized in the cardiac atria, increases GFR through vasodilatation of the afferent arterioles and vasoconstriction of the efferent arterioles, inhibits reabsorption of sodium, and redistributes renal medullary blood flow, resulting in an improved supply and reduced demand of oxygen in the tubules. Urodilatin is synthesized in the renal tubular cells by differential processing from the same precursor as ANP and has similar biologic effects. Plasma ANP levels rise during endotoxic shock in the rat, resulting in an increased diuresis and natriuresis (80). Experimental Studies. Exogenous administration of ANP increased RBF, GFR, and diuresis and improved renal pathologic changes in different experimental models of ischemic ARF (81). In LPS-induced ARF in the rat, urodilatin induced a fall in BP but increased GFR, diuresis, and natriuresis (82). In contrast, ANP did not affect these parameters in a similar model of endotoxemia in the rat (83). Clinical Studies. In a noncontrolled study of 11 patients who developed ARF after cardiac surgery, long-term (>48-h) ANP infusion improved RBF and GFR (84). An open-label study of 53 patients with ARF showed that patients receiving ANP had transient increases in creatinine clearance during the infusion of the peptide (24-h) and a decreased need for dialysis as compared with control patients (85). In contrast, in a randomized placebo-controlled trial including 504 critically ill patients with ARF (31% with sepsis), a 24-h infusion of the synthetic ANP anaritide did not improve the overall rate of dialysis-free survival (81). A subgroup analysis indicated that anaritide improved dialysis-free survival rate in oliguric patients by reducing the need for dialysis but not by lowering mortality. In non-oliguric patients, however, anaritide worsened dialysis-free survival. To further examine the potential benefit of anaritide in oliguric patients, a randomized placebo-controlled trial was conducted in 222 oliguric ARF patients (35% with sepsis) (86). Anaritide (24-h) conferred a nonsignificant trend toward improved 14-d and 21-d dialysis-free survival, but 60-d mortality rates were similar to placebo. The study was criticized for administering anaritide too late, too shortly, and at an excessive dose, the latter leading to hypotension and jeopardizing renal perfusion. In