Pharmacologic treatment of acute renal failure in sepsis - SASSiT

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Pharmacologic treatment of renal failure De Vriese and Bourgeois 475 Specifically for the kidney, passive immunization to TNF- prevented renal cortical damage during endotoxemia in rhesus monkeys [4]. In mice, both a TNFsoluble receptor [5] and a targeted deletion of TNF receptor-1 [6•] conferred protection against lipopolysaccharide-induced renal failure. In patients with septic shock, elevated levels of soluble TNF receptors are independent predictors for the development of ARF and death [7]. However, more than 10 large phase III trials with neutralizing monoclonal anti–TNF- antibodies and soluble TNF receptor fusion proteins failed to show survival benefits in patients with sepsis [3]. The monoclonal anti–TNF- antibody afelimomab conferred a 6.9% absolute and 14.3% relative reduction in riskadjusted mortality in septic patients with interleukin-6 concentrations of more than 1000 pg/mL [8]. In another study, however, afelimomabimparted only a small and nonsignificant survival benefit in a similar patient population [9]. In conclusion, despite the apparent success of anti-TNF therapies in animal models with prevention of both mortality and renal failure, these strategies have yielded disappointing results in humans. Inhibition of platelet-activating factor Serum and urinary concentrations of PAF are elevated in patients with sepsis and correlate with the severity of ARF [10]. Intrarenal infusion of PAF in the rat results in renal vasoconstriction and a fall in glomerular filtration rate (GFR) [11,12]. Several structurally unrelated PAF antagonists prevented the adverse renal hemodynamic effects of endotoxemia in the rat [11,12]. In patients with septic shock, the administration of a PAF antagonist reduced the need for dialysis but not mortality rates [13]. Other studies similarly failed to demonstrate a reduction in mortality with a PAF antagonist [14,15]. Serum levels of PAF acetylhydrolase, an enzyme that inactivates PAF, are deficient in sepsis [16•]. Whereas a relatively small trial in 127 patients with severe sepsis reported a lower 28-day mortality in those treated with recombinant PAF acetylhydrolase [17], a much larger trial with the same molecule was discontinued prematurely after an interim analysis in more than 1250 patients failed to demonstrate an improved mortality [16•]. In conclusion, although experimental studies are encouraging, the value of PAF antagonism in humans is marginal at best. Steroids An increase in tissue corticosteroid levels during acute illness is an important protective response. Subnormal adrenal corticosteroid production during acute severe illness has been termed functional adrenal insufficiency to reflect the notion that hypoadrenalism can occur without obvious structural defects [18]. Recognition of adrenal insufficiency in patients in the ICU is problematic. Clinical diagnostic clues include hemodynamic instability despite adequate fluid resuscitation and ongoing evidence of inflammation without an obvious source and not responding to empirical treatment. At least among patients in septic shock [19], cortisol levels below 15 µg/dL or between 15 and 34 µg/dL and a poor response to corticotropin (9 µg/dL) appear to identify patients with corticosteroid insufficiency who will benefit from corticosteroid treatment. Cortisol levels greater than 34 µg/dL are unlikely to be correlated with adrenal insufficiency. Several studies have examined the use of corticosteroid therapy in sepsis. Short-term treatment of heterogeneous groups of patients with supraphysiologic doses of glucocorticoids (eg, 30 mg/kg/d methylprednisolone) conveys no benefit and may be harmful [20]. Pharmacologic glucocorticoid treatment (2 mg/kg/d methylprednisolone) does, however, reduce mortality among patients with unresolving acute respiratory syndrome [21,22], and early treatment with dexamethasone may improve the outcome in bacterial meningitis [23,24]. Several randomized trials of low-dose hydrocortisone replacement therapy have shown improvements in hemodynamics and the need for vasopressor therapy [25–28]. In the largest of these, including 300 patients [27••], 50 mg hydrocortisone every 6 hours and 50 µg fludrocortisone once daily for 7 days significantly reduced mortality without increasing adverse events. Whether mineralocorticoid replacement accounted for any of the beneficial effects is unclear. Treatment should be initiated at the time of diagnostic testing and should be stopped if the results do not indicate the presence of adrenal insufficiency. Further studies are needed to clarify specific situations in which replacement is beneficial and to determine the optimal dose and optimal duration of therapy [18]. Corticus, an ongoing European trial of hydrocortisone in patients with septic shock, should help answer these important questions. Inhibition of nitric oxide synthase In the kidney, endothelial nitric oxide synthase (NOS) plays a pivotal role in vascular relaxation, inhibition of leukocyte adhesion, and platelet aggregation. Ischemic kidneys are characterized by an impaired release of nitric oxide produced by endothelial NOS [29]. On the other hand, lipopolysaccharide and inflammatory cytokines upregulate inducible NOS (iNOS) expression in the kidney [30]. As a result of these opposing alterations in NOS expression, studies using nonselective NOS inhibitors have yielded contradictory results. N-nitro-L-arginine methyl ester (L-NAME) prevented hypoxic cellular damage in isolated proximal tubules [31]. In contrast with 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 endotoxemia [32] and exacerbated preglomerular vasoconstriction during Escherichia
476 Renal system coli bacteremia in the rat [33]. In ovine Pseudomonas aeruginosa sepsis, L omega-mono-methyl-arginine increased blood pressure and systemic vascular resistance and decreased cardiac output, whereas RBF remained unchanged [34]. N-methyl-L-arginine fully reversed the decrease in blood pressure and partially reversed the decrease in RBF occurring in dogs after lipopolysaccharide infusion [35]. Although results with selective iNOS inhibitors were anticipated to be less ambiguous, discrepant findings have also been reported. The selective iNOS inhibitor S-methyl-isothiourea prevented hypotension through systemic vasoconstriction and maintained cardiac output, and reduced the signs of renal dysfunction in rats challenged with lipopolysaccharide [36]. In contrast, the degree of renal failure after lipopolysaccharide infusion was similar in iNOS knockout mice compared with wild-type mice [5]. In a hyperdynamic porcine model of sepsis, L-NAME reduced GFR and increased sodium excretion and renal oxygen extraction, whereas S-methyl-isothiourea did not affect GFR [37]. Several small and uncontrolled clinical studies demonstrated that short-term nonselective NOS inhibition increased both blood pressure and systemic vascular resistance and decreased cardiac output in patients with septic shock [38–40]. However, beneficial effects on renal function were not reported. A randomized, placebocontrolled trial with L omega-mono-methyl-arginine was discontinued early because of an increased mortality in the treated group. In conclusion, the ubiquitous nature and the pleiotropic effects of the nitric oxide system and its complex alterations in sepsis and ARF likely explain why nonselective NOS inhibitors and selective iNOS inhibitors fail to show straightforward laudable effects. Endothelin antagonism In humans with sepsis, plasma ET-1 levels are markedly elevated and correlate with morbidity and mortality [41]. Pretreatment with a nonselective ET receptorantagonist, blocking both ET A and ET B receptors, did not improve hypotension but increased RBF, creatinine clearance, and diuresis in canine endotoxemia [42]. Another nonselective ET receptor-antagonist induced a significant fall in blood pressure but prevented the reduction in RBF and GFR during endotoxic shock in neonatal piglets [43]. Further, an anti–ET-1 antibody improved renal function after endotoxin injection in rats [44]. In contrast, renal hemodynamics were unaffected by a nonselective ET receptor-antagonist in porcine endotoxic shock [45] and by a selective ET A receptor-antagonist in conscious rats subjected to lipopolysaccharide infusion [46]. So far, no studies with ET receptor-antagonists have been performed in patients with sepsis. Natriuretic peptides Exogenous administration of atrial natriuretic peptide (ANP) increased RBF, GFR, and diuresis and improved renal pathologic changes in different experimental models of ischemic ARF [47]. Urodilatin, which is synthesized in the renal tubular cells by differential processing from the same precursor as ANP, induced a fall in blood pressure but increased GFR, diuresis, and natriuresis in lipopolysaccharide-induced ARF in the rat [48]. In contrast, ANP did not affect these parameters in a similar model of endotoxemia in the rat [49]. In an open-label study of 53 patients with ARF, ANP resulted in a transient increase in creatinine clearance and a decreased need for dialysis [50]. In contrast, in a randomized, placebo-controlled trial including 504 critically ill patients with ARF (31% with sepsis), the synthetic ANP anaritide did not improve the overall rate of dialysis-free survival [47]. In 222 oliguric ARF patients (35% with sepsis), anaritide conferred a nonsignificant trend toward improved 14-day and 21-day dialysis-free survival, but 60- day mortality rates were similar to those with placebo [51]. In two randomized, placebo-controlled trials in critically ill patients with ARF, urodilatin did not improve renal function or reduce the need for renal replacement therapy [52,53]. In conclusion, there is no convincing evidence to support the use of natriuretic peptides as adjunctive treatment in ARF. Inhibition of leukocyte adhesion The recruitment of circulating leukocytes into a tissue is directed by specific adhesive interactions between the leukocyte and the vascular endothelium. Selectins (Lselectin, P-selectin, and E-selectin) and their carbohydrate-containing ligands mediate the initial contact between the leukocyte and the endothelium. Firm adherence and transendothelial migration are mediated by interactions between integrins on the leukocyte surface (eg, CD11a, CD11b) and their immunoglobulin-like receptors on the endothelium (eg, ICAM-1). During sepsis, leukocytes are known to infiltrate the kidneys and contribute to renal dysfunction. Leukocytes release reactive oxygen species and enzymes, which may directly injure cells. The production of cytokines attracts additional inflammatory cells and upregulates adhesion molecules, creating a cycle of injury. Release of vasoconstrictor arachidonic acid metabolites and physical congestion of medullary capillaries contribute to persistent hypoxia. Upregulation of CD11bon neutrophils independently predicted the development of ARF after cardiopulmonary bypass [54]. Treatment of experimental animals with anti–ICAM-1 antibodies [55,56] or with antisense oligonucleotides for ICAM-1 [57] provided protection from ischemic ARF. ICAM-1 knockout mice appeared resistant to acute renal ischemic injury [56]. Similarly,
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Pharmacologic treatment of acute renal failure in sepsis - SASSiT

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