Pharmacologic treatment of acute renal failure in sepsis - SASSiT

Pharmacologic treatment of acute renal failure in sepsis
An S. De Vriese a and Marc Bourgeois b
The pathophysiology of acute renal failure in sepsis is complex
and includes intrarenal vasoconstriction, infiltration of
inflammatory cells in the renal parenchyma, intraglomerular
thrombosis, and obstruction of tubuli with necrotic cells and
debris. Attempts to interfere pharmacologically with these
dysfunctional pathways, including inhibition of inflammatory
mediators, improvement of renal hemodynamics by amplifying
vasodilator mechanisms and blocking vasoconstrictor
mechanisms, and administration of growth factors to
accelerate renal recovery, have yielded disappointing results in
clinical trials. Interruption of leukocyte recruitment is a potential
promising approach in the treatment of septic acute renal
failure, but no data in humans are presently available. Activated
protein C and steroid replacement therapy have been shown
to reduce mortality in patients with sepsis and are now
accepted adjunctive treatment options for sepsis in general.
Keywords
Acute renal failure, sepsis
Curr Opin Crit Care 9:474–480. © 2003 Lippincott Williams & Wilkins.
a Renal Unit and b Department of Critical Care Medicine, AZ Sint-Jan AV, Brugge,
Belgium
Correspondence to An De Vriese, Renal Unit, AZ Sint-Jan AV, Ruddershove, 10
B-8000, Brugge, Belgium
Tel: +32 50452202; fax: +32 50452299; e-mail: an.devriese@azbrugge.be
Current Opinion in Critical Care 2003, 9:474–480
Abbreviations
ANP atrial natriuretic peptide
ARF acute renal failure
ET endothelin
GFR glomerular filtration rate
IGF insulin-like growth factor
iNOS inducible nitric oxide synthase
L-NAME N-nitro-L-arginine methyl ester
NOS nitric oxide synthase
PAF platelet-activating factor
RBF renal blood flow
TFPI tissue factor pathway inhibitor
TNF tumor necrosis factor
© 2003 Lippincott Williams & Wilkins
1070-5295
474
Introduction
The development of acute renal failure (ARF) is common
in patients with sepsis and carries an ominous prognosis.
Sepsis is a complex clinical syndrome characterized
by widespread activation of the inflammatory,
coagulation, and fibrinolytic cascades. As sepsis persists,
an anti-inflammatory response is mounted, resulting in
immune paralysis [1]. A broad array of humoral mediators
are released in the systemic circulation, including inflammatory
and anti-inflammatory cytokines, lipid mediators
such as platelet-activating factor (PAF) and arachidonic
acid metabolites, endothelin (ET)-1, and complement
components [1]. Systemic hypotension, resulting in renal
hypoperfusion and hypoxia, is a contributing factor—but
certainly not the sole factor—in septic ARF. Intrarenal
vasoconstriction, caused by an imbalance between vasodilatory
and vasoconstrictive substances, results in a decline
in renal blood flow (RBF) and abnormalities in
intrarenal blood flow distribution that predominantly affect
the outer medulla. Inflammatory cells infiltrate the
kidney, causing local damage by release of superoxidederived
free radicals and lysosomal enzymes and further
production of inflammatory cytokines. Leukocyteendothelial
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
tubular obstruction and backleak. Recovery from ARF
requires clearance of necrotic tubular cells and debris
and regeneration and repair of the nonfatally injured
cells.
This article discusses attempts to interfere pharmacologically
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. The discussion of supportive treatment,
including fluid management, use of vasopressors and diuretics,
and dialytic treatment, falls beyond the scope
and space limitations of this article but has recently been
discussed elsewhere [2].
Antitumor necrosis factor- therapy
Antibodies against tumor necrosis factor (TNF) protect
against morbidity and mortality from both Gram-positive
and Gram-negative sepsis in diverse animal models [3].

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,

Pharmacologic treatment of renal failure De Vriese and Bourgeois 477
anti-CD11a and anti-CD11bantibodies decreased injury
after experimental renal ischemia in the rat [58]. Further,
mice deficient for the Src family kinases Hck and Fgr,
required for integrin signal transduction, were resistant
to the lethal effects of lipopolysaccharide injection and
had a marked reduction in renal damage [59]. Sialyl-
Lewis X, a soluble ligand for selectins, and an anti–Pselectin
antibody attenuated renal dysfunction and histopathologic
changes in lipopolysaccharide-induced ARF
in rabbits [60]. Finally, E-selectin, P-selectin, and E/Pselectin
knockout mice were resistant to lethality and
renal dysfunction during septic peritonitis [61•]. No human
trials with antibodies to leukocyte adhesion molecules
are presently available. In an opposite line of reasoning,
however, filgrastim (granulocyte colonystimulating
factor) was administered to patients with
severe sepsis to enhance neutrophil production and function.
Although the intervention did not improve mortality,
fortunately no adverse effects on end-organ function
were observed [62].
Inhibitors of coagulation
Tissue factor pathway inhibitor
Diffuse intravascular coagulation in sepsis is caused by
tissue factor-mediated thrombin generation. Tissue factor
forms a complex with factor VIIa, which cleaves factor
IX and factor X, initiating thrombin generation. Tissue
factor is inhibited by a natural anticoagulant, tissue factor
pathway inhibitor (TFPI). Specific blockade of the tissue
factor–factor VIIa complex, with either TFPI or a
site-inactivated factor VIIa, prevented renal injury during
E. coli sepsis in baboons. Fibrin deposition in glomeruli
and tubuli, and vessels occluded by fibrin clots,
were identified in control animals but were absent in
treated animals [63]. Similar results were obtained when
the tissue factor pathway was blocked only after Gramnegative
sepsis was well established [64•]. A phase II
trial, comparing placebo and recombinant TFPI in 210
patients with severe sepsis, showed a trend toward mortality
reduction in the recombinant TFPI-treated group
[65]. However, a recently completed phase III trial failed
to demonstrate a benefit of TFPI in patients with severe
sepsis or septic shock [66••].
Antithrombin
Antithrombin blocks several proteases involved in coagulation,
but its inhibitory effect is most powerful against
factor Xa and thrombin. Plasma levels of antithrombin
are usually markedly reduced in patients with sepsis, and
this reduction is associated with an increased mortality
[67]. Melagatran, a low molecular weight thrombin inhibitor,
protected against renal dysfunction in a porcine
model of endotoxemia [68]. A meta-analysis aggregating
data from 122 patients with sepsis supplemented with
antithrombin reported a 22% nonsignificant decrease in
mortality in the treated patients [69]. However, in a
double-blind, placebo-controlled, multicenter trial in
2314 patients with severe sepsis and septic shock, highdose
antithrombin had no effect on 28-day mortality and
was associated with an increased risk of hemorrhage
when coadministered with heparin [67]. In a predefined
subgroup of patients not receiving heparin, there was a
trend toward a reduced 28-day and 90-day mortality [67].
Activated protein C
Protein C is activated by the thrombin–thrombomodulin
complex on endothelial cells. Activated protein C inhibits
thrombin generation by inactivating factor Va and factor
VIIIa. Besides its effects on coagulation, activated
protein C has direct anti-inflammatory properties, including
impairment of leukocyte adhesion to the endothelium
by binding selectins and inhibition of the production
of inflammatory cytokines by monocytes.
Further, it stimulates the fibrinolytic response by inhibiting
plasminogen-activator inhibitor type 1 [70]. Reduced
levels of protein C are found in patients with
sepsis and are associated with a fatal outcome [70]. The
species specificity of activated protein C has limited its
testing as a treatment for sepsis to studies in baboons. In
these animals, administration of activated protein C prevented
the procoagulant and lethal effects of Gramnegative
sepsis [71]. In a randomized, multicenter trial
conducted in 1690 patients with severe sepsis, recombinant
human activated protein C significantly reduced
mortality [70]. Activated protein C is currently the first
biologic agent approved by the US Food and Drug Administration
for the treatment of sepsis [66••]. Because
the benefit of activated protein C consistently increased
with the risk of death, the Food and Drug Administration
has restricted its use to patients with an Acute Physiology
and Chronic Health Evaluation score of 25 or more
until further data are available [66••]. In Europe, activated
protein C will be approved for patients with severe
sepsis and two or more failing organs. Activated protein
C also decreased interleukin-6 levels, a finding consistent
with its known anti-inflammatory activity [70]. Because
there exists an intense and complex crosstalk between
the proinflammatory, coagulation, and fibrinolytic
networks, the success of activated protein C may hinge
on its combined effects on coagulation, fibrinolysis, and
inflammation rather than its anticoagulant action alone.
Growth factors
Regeneration of tubular cells requires the participation
of growth factors. In rat models of renal ischemia, exogenous
administration of epidermal growth factor [72] and
insulin-like growth factor I (IGF-I) [73,74] buttressed
the recovery of renal function and reduced mortality. In
addition, IGF-I is a downstream mediator of growth hormone
and has potent anabolic effects. IGF-I reduced
protein catabolism and stimulated protein synthesis in
skeletal muscle of rats with ARF [73]. In contrast with
the beneficial effects in rat models, epidermal growth
factor failed to affect renal ischemic injury in the pig, a

478 Renal system
model of ARF that more closely resembles the human
condition [75]. In fact, animals treated with epidermal
growth factor had higher serum creatinine levels than the
control group [75]. In a multicenter, randomized, placebo-controlled
trial, IGF-I did not reduce time to renal
recovery or mortality rates in 72 critically ill patients with
ARF [76]. Anuric patients who received IGF-I even
tended to have slower rates of improvement in urine
output and in GFR than placebo-treated subjects, hinting
at potential adverse effects of IGF-I. In 54 patients
undergoing suprarenal aorta or renal artery surgery, no
differences in serum creatinine at time of discharge,
length of ICU and hospital stay, or incidence of dialysis
and death were observed between IGF-I and placebotreated
subjects, although a smaller proportion of the
former group had a postoperative decline in renal function
[77]. Several small and uncontrolled studies reported
that growth hormone administration to critically
ill patients with sepsis resulted in an improvement of
nitrogen balance commensurate with an increase in
IGF-I levels [78]. A randomized, placebo-controlled trial
involving 247 patients in the ICU revealed, however,
that high-dose growth hormone therapy is associated
with increased morbidity and mortality [78].
In conclusion, despite ample evidence that growth factors
accelerate renal recovery in experimental ARF in the
rat, a study in a large animal model more representative
of human ARF and several clinical studies in critically ill
patients demonstrate no beneficial or even detrimental
effects.
Conclusion
Several decades of research efforts have been successful
in unraveling the complex pathophysiology of sepsis and
ARF and have resulted in the development of different
pharmacologic interventions that are very effective in
experimental models. With the exception of low-dose
corticosteroids and activated protein C (APC), which are
now accepted supportive treatment options for sepsis in
general, the clinical application of these therapies has
bitterly failed and has consumed precious resources. Although
multiple explanations have been advocated, the
most important is perhaps the dynamic nature of sepsis
and ARF. The relative role of the different mediators
varies with time; consequently, therapeutic strategies
that are appropriate early in the disease process may lose
their efficacy later. Future studies should be directed at
elucidating which patients need enhancement or inhibition
of immune response, depending on genetic polymorphisms,
the duration of disease, and the characteristics
of the particular pathogen. In the meantime, clear
guidelines on basic therapeutic attitudes in the management
of ARF, such as the optimal fluid resuscitation
regimen, use of diuretics, dose of dialysis, and timing of
initiation of dialysis, have not been developed. These
issues equally deserve our attention.
References and recommended reading
Papers of particular interest, published within the annual period of review,
have been highlighted as:
• Of special interest
•• Of outstanding interest
1 Cohen J: The immunopathogenesis of sepsis. Nature 2002, 420:885–891.
2 De Vriese AS: Prevention and treatment of acute renal failure in sepsis. J Am
Soc Nephrol 2003, 14:792–805.
3 Reinhart K, Karzai W: Anti-tumor necrosis factor therapy in sepsis: updateon
clinical trials and lessons learned. Crit Care Med 2001, 29(suppl
7):S121–S125.
4 Fiedler VB, Loof I, Sander E, et al.: Monoclonal antibody to tumor necrosis
factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab
Clin Med 1992, 120:574–588.
5 Knotek M, Rogachev B, Wang W, et al.: Endotoxemic renal failure in mice:
role of tumor necrosis factor independent of inducible nitric oxide synthase.
Kidney Int 2001, 59:2243–2249.
6 Cunningham PN, Dyanov HM, Park P, et al.: Acute renal failure in endotoxemia
• is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol
2002, 168:5817–5823.
Unravels the pathophysiologic role of TNF in septic ARF.
7 Iglesias J, Marik PE, Levine JS, Norasept II Study Investigators: Elevated serum
levels of the type I and type II receptors for tumor necrosis factor-alpha as
predictive factors for ARF in patients with septic shock. Am J Kidney Dis
2003, 41:62–75.
8 Panacek E, Marshall J, Fischkoff S, et al., and MONARCS Study Group: Neutralization
of TNF by a monoclonal antibody improves survival and reduces
organ dysfunction in human sepsis: results of the MONARCS trial [abstract].
Chest 2000, 118(suppl 4):88S.
9 Reinhart K, Menges T, Gardlund B, et al.: Randomized, placebo-controlled
trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory
response during severe sepsis: the RAMSES Study. Crit Care
Med 2001, 29:765–769.
10 Mariano F, Guida G, Donati D, et al.: Production of platelet-activating factor in
patients with sepsis-associated acute renal failure. Nephrol Dial Transplant
1999, 14:1150–1157.
11 Wang J, Dunn MJ: Platelet-activating factor mediates endotoxin-induced
acute renal insufficiency in rats. Am J Physiol 1987, 253:F1283–F1289.
12 Tolins JP, Vercellotti GM, Wilkowske M, et al.: Role of platelet activating factor
in endotoxemic acute renal failure in the male rat. J Lab Clin Med 1989,
113:316–324.
13 Poeze M, Froon AH, Ramsay G, et al.: Decreased organ failure in patients with
severe SIRS and septic shock treated with the platelet-activating factor antagonist
TCV-309: a prospective, multicenter, double-blind, randomized
phase II trial. TCV-309 Septic Shock Study Group. Shock 2000, 14:421–
428.
14 Vincent JL, Spapen H, Bakker J, et al.: Phase II multicenter clinical study of the
platelet-activating factor receptor antagonist BB-882 in the treatment of sepsis.
Crit Care Med 2000, 28:638–642.
15 Dhainaut JF, Tenaillon A, Hemmer M, et al.: Confirmatory platelet-activating
factor receptor antagonist trial in patients with severe Gram-negative bacterial
sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter
trial. BN 52021 Sepsis Investigator Group. Crit Care Med 1998,
26:1963–1971.
16 Rabinovici R: Platelet activating factor inhibition in sepsis: the end? Crit Care
• Med 2003, 31:1861–1862.
Critically reviews the trials on PAF inhibition in sepsis.
17 Schuster DP, Metzler M, Opal S, et al., Pafase ARDS Prevention Study
Group: Recombinant platelet-activating factor acetylhydrolase to prevent
acute respiratory distress syndrome and mortality in severe sepsis: phase IIb,
multicenter, randomized, placebo-controlled, clinical trial. Crit Care Med
2003, 31:1612–1619.
18 Cooper MS, Steward PM: Corticosteroid insufficiency in acutely ill patients. N
Engl J Med 2003, 348:727–734.
19 Annane D, Sebille V, Troche G, et al.: A3-level prognostic classification in
septic shock based on cortisol levels and cortisol response to corticotropin.
JAMA 2000, 283:1038–1045.
20 Lamberts SWJ, Bruining HA, de Jong FH: Corticosteroid therapy in severe
illness. N Engl J Med 1997, 337:1285–1292.
21 Meduri GU, Headley AS, Golden E, et al.: Effect of prolonged methylprednis-

Pharmacologic treatment of renal failure De Vriese and Bourgeois 479
olone therapy in unresolving acute respiratory distress syndrome: a randomized
controlled trial. JAMA 1998, 280:159–165.
22 Meduri GU, Tolley EA, Chrousos GP, et al.: Prolonged methylprednisolone
treatment suppresses systemic inflammation in patients with unresolving
acute respiratory distress syndrome: evidence for inadequate endogenous
glucocorticoid secretion and inflammation-induced immune cell resistance to
glucocorticoids. Am J Respir Crit Care Med 2002, 165:983–991.
23 Lebel MH, Freij BJ, Syrogiannopoulos GA, et al.: Dexamethasone therapy for
bacterial meningitis: results of two double-blind, placebo-controlled trials. N
Engl J Med 1988, 319:964–971.
24 de Gans J, van de Beek D: Dexamethasone in adults with bacterial meningitis.
N Engl J Med 2002, 347:1549–1556.
25 Bollaert PE, Charpentier C, Levy B, et al.: Reversal of late septic shock with
supraphysiologic doses of hydrocortisone. Crit Care Med 1998, 26:645–
650.
26 Briegel J, Forst H, Haller M, et al.: Stress doses of hydrocortisone reverse
hyperdynamic septic shock: a prospective, randomized, double-blind, singlecenter
study. Crit Care Med 1999, 27:723–732.
27 Annane D, Sebille V, Charpentier C, et al.: Effect of treatment with low doses
•• of hydrocortisone and fludrocortisone on mortality in patients with septic
shock. JAMA 2002, 288:862–871.
Large randomized, controlled trial demonstrating efficacy of steroid replacement
therapy in sepsis.
28 Keh D, Boehnke T, Weber-Cartens S, et al.: Immunologic and hemodynamic
effects of “low-dose” hydrocortisone in septic shock: a double-blind, randomized,
placebo-controlled, crossover study. Am J Respir Crit Care Med 2003,
167:512–520.
29 Conger J, Robinette J, Villar A, et al.: Increased nitric oxide synthase activity
despite lack of response to endothelium-dependent vasodilators in postischemic
acute renal failure in rats. J Clin Invest 1995, 96:631–638.
30 Morrissey JJ, McCracken R, Kaneto H, et al.: Location of an inducible nitric
oxide synthase mRNA in the normal kidney. Kidney Int 1994, 45:998–1005.
31 Yu L, Gengaro PE, Niederberger M, et al.: Nitric oxide: a mediator in rat tubular
hypoxia/reoxygenation injury. Proc Natl Acad Sci USA1994,
91:1691–1695.
32 Shultz PJ, Raij L: Endogenously synthesized nitric oxide prevents endotoxininduced
glomerular thrombosis. J Clin Invest 1992, 90:1718–1725.
33 Spain DA, Wilson MA, Garrison RN: Nitric oxide synthase inhibition exacerbates
sepsis-induced renal hypoperfusion. Surgery 1994, 116:322–330.
34 Booke M, Hinder F, McGuire R, et al.: Nitric oxide synthase inhibition versus
norepinephrine in ovine sepsis: effects on regional blood flow. Shock 1996,
5:362–370.
35 Doursout MF, Kilbourn RG, Hartley CJ, et al.: Effects of N-methyl-L-arginine
on cardiac and regional blood flow in a dog endotoxin shock model. J Crit
Care 2000, 15:22–29.
36 Rosselet A, Feihl F, Markert M, et al.: Selective iNOS inhibition is superior to
norepinephrine in the treatment of rat endotoxic shock. Am J Respir Crit Care
Med 1998, 157:162–170.
37 Cohen RI, Hassell AM, Marzouk K, et al.: Renal effects of nitric oxide in endotoxemia.
Am J Respir Crit Care Med 2001, 164:1890–1895.
38 Petros A, Lamb G, Leone A, et al.: Effects of a nitric oxide synthase inhibitor
in humans with septic shock. Cardiovasc Res 1994, 28:34–39.
39 Avontuur JA, Tutein Nolthenius RP, van Bodegom JW, et al.: Prolonged inhibition
of nitric oxide synthesis in severe septic shock: a clinical study. Crit
Care Med 1998, 26:660–667.
40 Grover R, Zaccardelli D, Colice G, et al.: An open-label dose escalation study
of the nitric oxide synthase inhibitor, N(G)-methyl-L-arginine hydrochloride
(546C88), in patients with septic shock. Glaxo Wellcome International Septic
Shock Study Group. Crit Care Med 1999, 27:913–922.
41 Weitzberg E, Lundberg JM, Rudehill A: Elevated plasma levels of endothelin
in patients with sepsis syndrome. Circ Shock 1991, 33:222–227.
42 Mitaka C, Hirata Y, Yokoyama K, et al.: Improvement of renal dysfunction in
dogs with endotoxemia by a nonselective endothelin receptor antagonist. Crit
Care Med 1999, 27:146–153.
43 Chin A, Radhakrishnan J, Fornell L, et al.: Effects of tezosentan, a dual endothelin
receptor antagonist, on the cardiovascular and renal systems of neonatal
piglets during endotoxic shock. J Pediatr Surg 2002, 37:482–487.
44 Morise Z, Ueda M, Aiura K, et al.: Pathophysiologic role of endothelin-1 in
renal function in rats with endotoxin shock. Surgery 1994, 115:199–204.
45 Oldner A, Wanecek M, Goiny M, et al.: The endothelin receptor antagonist
bosentan restores gut oxygen delivery and reverses intestinal mucosal acidosis
in porcine endotoxin shock. Gut 1998, 42:696–702.
46 Gardiner SM, March JE, Kemp PA, et al.: Effects of the novel selective endothelin
ET(A) receptor antagonist, SB 234551, on the cardiovascular responses
to endotoxaemia in conscious rats. Br J Pharmacol 2001,
133:1371–1377.
47 Allgren RL, Marbury TC, Rahman SN, et al.: Anaritide in acute tubular necrosis.
Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med 1997,
336:828–834.
48 Schramm L, Heidbreder E, Lukes M, et al.: Endotoxin-induced acute renal
failure in the rat: effects of urodilatin and diltiazem on renal function. Clin
Nephrol 1996, 46:117–124.
49 Hiki N, Mimura Y: Atrial natriuretic peptide has no potential to protect against
endotoxin-induced acute renal failure in the absence of renal nerves. Endocr
J 1998, 45:75–81.
50 Rahman SN, Kim GE, Mathew AS, et al.: Effects of atrial natriuretic peptide in
clinical acute renal failure. Kidney Int 1994, 45:1731–1738.
51 Lewis J, Salem MM, Chertow GM, et al.: Atrial natriuretic factor in oliguric
acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney
Dis 2000, 36:767–774.
52 Herbert MK, Ginzel S, Muhlschlegel S, et al.: Concomitant treatment with
urodilatin (ularitide) does not improve renal function in patients with acute
renal failure after major abdominal surgery—a randomized controlled trial.
Wien Klin Wochenschr 1999, 111:141–147.
53 Meyer M, Pfarr E, Schirmer G, et al.: Therapeutic use of the natriuretic peptide
ularitide in acute renal failure. Ren Fail 1999, 21:85–100.
54 Rinder CS, Fontes M, Mathew JP, et al., Multicenter Study of Perioperative
Ischemia Research Group: Neutrophil CD11b upregulation during cardiopulmonary
bypass is associated with postoperative renal injury. Ann Thorac Surg
2003, 75:899–905.
55 Kelly KJ, Williams WW Jr, Colvin RB, et al.: Antibody to intercellular adhesion
molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U
S A 1994, 91:812–816.
56 Kelly KJ, Williams WW Jr, Colvin RB, et al.: Intercellular adhesion molecule-
1-deficient mice are protected against ischemic renal injury. J Clin Invest
1996, 97:1056–1063.
57 Haller H, Dragun D, Miethke A, et al.: Antisense oligonucleotides for ICAM-1
attenuate reperfusion injury and renal failure in the rat. Kidney Int 1996,
50:473–480.
58 Rabb H, Mendiola CC, Dietz J, et al.: Role of CD11a and CD11b in ischemic
acute renal failure in rats. Am J Physiol 1994, 267:F1052–F1058.
59 Lowell CA, Berton G: Resistance to endotoxic shock and reduced neutrophil
migration in mice deficient for the Src-family kinases Hck and Fgr. Proc Natl
Acad Sci USA1998, 95:7580–7584.
60 Hayashi H, Imanishi N, Ohnishi M, et al.: Sialyl Lewis X and anti-P-selectin
antibody attenuate lipopolysaccharide-induced acute renal failure in rabbits.
Nephron 2001, 87:352–360.
61 Matsukawa A, Lukacs NW, Hogaboam CM, et al.: Mice genetically lacking
• endothelial selectins are resistant to the lethality in septic peritonitis. Exp Mol
Pathol 2002, 72:68–76.
Demonstrates beneficial effects of inhibition of leukocyte recruitment on both renal
dysfunction and mortality in an experimental model of septic ARF.
62 Root RK, Lodato RF, Patrick W, et al., Pneumonia Sepsis Study Group: Multicenter,
double-blind, placebo-controlled study of the use of filgrastim in patients
hospitalized with pneumonia and severe sepsis. Crit Care Med 2003,
31:367–373.
63 Welty-Wolf KE, Carraway MS, Miller DL, et al.: Coagulation blockade prevents
sepsis-induced respiratory and renal failure in baboons. Am J Respir
Crit Care Med 2001, 164:1988–1996.
64 Carraway MS, Welty-Wolf KE, Miller DL, et al.: Blockade of tissue factor:
treatment for organ injury in established sepsis. Am J Respir Crit Care Med
2003, 167:1200–1209.
Experimental evidence for the efficacy of late treatment with TFPI in sepsis.
65 Healy DP: New and emerging therapies for sepsis. Ann Pharmacother 2002,
36:648–654.
66 Warren HS, Suffredini AF, Eichacker PQ, et al.: Risks and benefits of activated
protein C treatment for severe sepsis. N Engl J Med 2002, 347:1027–
••
1030.
Critical discussion of the value of APC treatment in sepsis.
67 Warren BL, Eid A, Singer P, et al., KyberSept Trial Study Group: Caring for

480 Renal system
the critically ill patient: high-dose antithrombin III in severe sepsis: a randomized
controlled trial. JAMA 2001, 286:1869–1878.
68 Eriksson M, Larsson A, Saldeen T, et al.: Melagatran, a low molecular weight
thrombin inhibitor, counteracts endotoxin-induced haemodynamic and renal
dysfunctions in the pig. Thromb Haemost 1998, 80:1022–1026.
69 Eisele B, Lamy M, Thijs LG, et al.: Antithrombin III in patients with severe
sepsis: a randomized, placebo-controlled, double-blind multicenter trial plus a
meta-analysis on all randomized, placebo-controlled, double-blind trials with
antithrombin III in severe sepsis. Intensive Care Med 1998, 24:663–672.
70 Bernard GR, Vincent JL, Laterre PF, et al., Recombinant Human Protein C
Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group: Efficacy
and safety of recombinant human activated protein C for severe sepsis. N
Engl J Med 2001, 344:699–709.
71 Taylor FB Jr, Chang A, Esmon CT, et al.: Protein C prevents the coagulopathic
and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest
1987, 79:918–925.
72 Humes HD, Cieslinski DA, Coimbra TM, et al.: Epidermal growth factor enhances
renal tubule cell regeneration and repair and accelerates the recovery
of renal function in postischemic acute renal failure. J Clin Invest 1989,
84:1757–1761.
73 Ding H, Kopple JD, Cohen A, et al.: Recombinant human insulin-like growth
factor-I accelerates recovery and reduces catabolism in rats with ischemic
acute renal failure. J Clin Invest 1993, 91:2281–2287.
74 Hirschberg R, Ding H: Mechanisms of insulin-like growth factor-I-induced accelerated
recovery in experimental ischemic acute renal failure. Miner Electrolyte
Metab 1998, 24:211–219.
75 Killion D, Canfield C, Norman J, et al.: Exogenous epidermal growth factor
fails to accelerate functional recovery in the autotransplanted ischemic pig
kidney. J Urol 1993, 150:1551–1556.
76 Hirschberg R, Kopple J, Lipsett P, et al.: Multicenter clinical trial of recombinant
human insulin-like growth factor I in patients with acute renal failure.
Kidney Int 1999, 55:2423–2432.
77 Franklin SC, Moulton M, Sicard GA, et al.: Insulin-like growth factor I preserves
renal function postoperatively. Am J Physiol 1997, 272:F257–F259.
78 Takala J, Ruokonen E, Webster NR, et al.: Increased mortality associated with
growth hormone treatment in critically ill adults. N Engl J Med 1999,
341:785–792.