sepsis and the kidney.pdf - SASSiT

Crit Care Clin 21 (2005) 211 – 222
Sepsis and the Kidney
Jennifer Klenzak, MD, Jonathan Himmelfarb, MD*
Division of Nephrology, Maine Medical Center, 22 Bramhall Street, Portland, ME 04102, USA
Acute renal failure (ARF) affects up to 20% of critically ill patients; sepsis
accounts for most ARF cases in these patients. ARF occurs in 51% of patients
with septic shock and positive blood cultures [1]. Approximately 700,000
hospitalized patients develop sepsis each year in the United States, and they
account for 210,000 deaths. Between 5% and 51% of these patients develop
ARF, and the risk increases with positive blood cultures and worsening clinical
signs of sepsis. The last 20 years have witnessed significant improvements
in the care of critically ill patients, leading to improved outcomes in many
diseases. Unfortunately, the septic patient with ARF has not benefited from
technologic and therapeutic advances to the same degree. Mortality remains
unacceptably high for septic patients with ARF, hovering at 70%. The development
of ARF in these patients portends a poor outcome. It remains unclear,
however, whether ARF plays a significant role in the subsequent development
of multiple organ systems failure (MOSF), through its effects on metabolic
homeostasis, or if ARF is merely a marker on the road to the loss of life.
Patients who develop ARF in the setting of critical illness are more likely to
die than dialysis-dependent patients admitted to the ICU, suggesting that the
outcome associated with the development of new renal dysfunction is based on
the pathophysiology of sepsis and systemic dysregulation, rather than merely
the renal dysfunction itself [2].
* Corresponding author.
E-mail address: himmej@mmc.org (J. Himmelfarb).
0749-0704/05/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2005.01.002
criticalcare.theclinics.com

212
klenzak & himmelfarb
Pathophysiology
Tubular epithelium and acute tubular necrosis
The clinical syndrome of ARF in the setting of critical illness, manifested by
rising serum creatinine and decreasing urine output, results from injury to the
tubular epithelial cells, or acute tubular necrosis (Fig. 1). Ischemic or toxic injury
primarily affects this renal compartment, both because this area is most dependent
on downstream blood flow, and these cells are highly metabolically active,
engaged in solute and water transport. The tubular epithelial cells most vulnerable
to ischemia line the S3 segment of the proximal tubule.
Lethal injury to these cells (necrosis or apoptosis) leads to loss of cell adhesion
to the tubular basement membrane and subsequent shedding into the lumen. The
denuded cells appear in the urine intact as tubular epithelial cell casts, or they
may degrade leading to excretion of granular casts, both of which are typically
found in the urine of patients with acute tubular necrosis. Such casts may cause
micro-obstruction to urine flow. The damaged tubular basement membrane may
fill with cast material, cellular debris, and Tamm-Horsfall protein. Sublethal
injury results in loss of the brush border, which is the site of much energyconsuming
metabolic activity.
The mechanisms of injury to tubular epithelial cells in sepsis are difficult to
reproduce in the laboratory. Laboratory models of acute tubular necrosis have
Pathophysiology of Ischemic Acute Renal Failure
MICROVASCULAR
Glomerular
Medullary
Vasoconstriction in response to:
endothelin, adenosine,
angiotensin II, thromboxane A2,
leukotrienes, sympathetic nerve
activity
Vasodilation in response to:
nitric oxide, PGE2, acetylcholine
bradykinin
Endothelial and vascular smooth
muscle cell structural damage
Leukocyte-Endothelial adhesion
vascular obstruction, leukocyte
activation, and inflammation
O 2
Inflammatory
and
vasoactive
mediators
TUBULAR
Cytoskeletal breakdown
Loss of polarity
Apoptosis and Necrosis
Desquamation of viable
and necrotic cells
Tubular obstruction
Backleak
Fig. 1. Pathophysiology of ischemic acute renal failure. PGE2, prostaglandin E 2 .

sepsis and the kidney 213
relied on either ischemic or toxic injury to simulate ARF. More than ischemia or
toxicity, however, is responsible for the cellular signaling to apoptosis in sepsis.
In sepsis the loss of autoregulatory pathways, an imbalance between inflammation
and anti-inflammatory cytokines, thrombosis and bleeding, vasodilation and
vasoconstriction, oxidation and reduction, catabolic and anabolic activity, and
dysregulation of enzyme activity all contribute to organ dysfunction through
mechanisms not yet fully elucidated. It is in this pathologic milieu that kidney
function deteriorates in sepsis, which further adds the stress of fluid and
electrolyte imbalance, waste clearance, and platelet dysfunction.
Alterations in renal blood flow
Intrarenal hemodynamic changes
Systemic hypotension leads to autoregulation of local hemodynamics within
the kidney. Afferent arteriolar vasoconstriction decreases capillary hydrostatic
pressure and limits the perfusion of capillary beds. Impaired perfusion of capillary
beds reduces filtration surface and leads to some reabsorption of interstitial
fluid into the capillaries, as long as intravascular oncotic pressure remains constant
or increases. Additionally, metabolic activity and waste products increase
extracellular osmolality leading to fluid extravasation from cells. For these
reasons, intravascular and interstitial volume increase at the expense of intracellular
volume.
In the kidney, constriction of the afferent arterioles decreases glomerular
perfusion. With less glomerular perfusion, less filtrate is generated. Micropuncture
studies show that endotoxin decreases filtration rate and glomerular
flow with increased renal arteriolar resistance [3]. This compensatory response
may be somewhat protective in that it leads to less ATP-requiring work from the
highly metabolically active tubular epithelial cells. Downstream of the glomerular
capillary bed, decreased blood flow to the efferent arteriole reduces perfusion of
the vasa recta. The vasa recta supply nutrients and oxygen, and serve as a conduit
for the return of fluid and electrolytes to the systemic circulation from the
relatively hypoxic medulla. The S3 segment of the proximal tubule, or pars recta,
is highly active and ATP-requiring. This segment is sensitive to alterations in
blood flow because it depends on the deoxygenated blood of this microcirculation
for its oxygen supply. For this reason, it is usually the first tubular
segment to be injured from decreases in renal blood flow (RBF) or hypoxemia
[4,5].
Hypoxemia or decreased RBF is likely one of many mechanisms of renal
injury in the setting of sepsis. It has also been suggested that renal ischemia
related to decreased renal perfusion is not the main mechanism of ARF in sepsis.
Animal models have shown increases in renal perfusion in the setting of
hyperdynamic shock. ARF can occur in the setting of preserved or increased RBF

214
klenzak & himmelfarb
in the setting of hyperdynamic sepsis. Although the role of hypoperfusion needs
elucidation in the setting of sepsis, these studies certainly support the hypothesis
that mediators of cellular injury, rather than lack of blood, play a larger role in the
pathophysiology of ARF [6].
Vasopressors and acute renal failure
In the setting of hypodynamic septic shock, compensatory increases in
systemic vascular resistance become disabled, leading to pressor desensitivity
and refractory hypotension without local autoregulation of the vital organs.
Clinical concerns regarding the use of vasopressor therapies, which are known
to induce vasoconstriction in the setting of ARF, are set aside by the supremacy
of increasing systemic blood pressure to levels that continue to perfuse the
remainder of the vital organs. Norepinephrine infusion may, in fact, increase
RBF. Several animal studies have demonstrated increases in RBF with the use of
norepinephrine infusion [7–12]. Recent work by Di et al [13] demonstrated that
norepinephrine infusion in septic sheep induced an increase in RBF, countering
concern that vasoconstrictors worsen blood delivery to the renal parenchyma in
the setting of vasodilatory shock.
Nitric oxide synthase
In contrast, in hyperdynamic shock RBF is preserved, with apparent
redistribution of flow from cortex to medulla, maintaining oxygen delivery to
the most vulnerable portions of the renal parenchyma, while also decreasing
the work of the tubules. This redistribution of blood flow coincides with an increase
in nitric oxide (NO) in the medulla [14]. Inducible NO synthase (iNOS)
can be expressed locally, in glomerular mesangial cells and endothelial cells,
after stimulation with proinflammatory cytokines, including tumor necrosis factor
(TNF) and interleukin (IL)-1, and endotoxin [15]. Nonselective or selective
blockade of NOS decreases RBF while increasing mean arterial pressure. This
suggests that iNOS plays a role in maintaining RBF in the setting of shock
through its vasodilatory effects at the afferent arteriole. Despite increases in
iNOS, renal vasoconstriction can be seen in the setting of systemic vasodilation.
The mechanism of vasodilation by NO is dependent on the synthesis of cyclic
guanosine monophosphate by soluble guanylate cyclase. Studies of lipopolysaccharide
(LPS) stimulation in mice leading to shock and ARF have demonstrated
a decrease in cyclic guanosine monophosphate to basal levels at 24 hours,
despite an early rise in and sustained iNOS levels, suggesting that desensitization
of soluble guanylate cyclase results in loss of regulatory vasodilation in the kidney
[16]. NOS inhibition in animal models of endotoxemia results in glomerular
thrombosis and declines in creatinine clearance. The glomerular thrombosis
in the setting of NOS inhibition seems related to the antithrombotic qualities of

sepsis and the kidney 215
NOS, by inhibiting leukocyte interactions with endothelial cells and inhibiting
platelet aggregation [17].
Soluble and local mediators
Endothelins
The production of endothelins, which are potent vasoconstrictors, by endothelial,
mesangial and tubular cells is stimulated by proinflammatory cytokines,
including TNF. The vasoconstrictors vasopressin and angiotensin II also
stimulate endothelin release. Endothelins cause vigorous constriction of the
afferent and efferent arterioles, and mesangial cell contraction. The effects of
endothelin may be secondary to its induction of platelet-activating factor (PAF)
synthesis in the mesangium or thromboxane A 2 by the endothelium. Additionally,
endothelin induces some vasodilators, counteracting its vasoconstricting effect,
including prostacyclin, NO, and prostaglandin E 2 . Two endothelin receptors are
active in the renal parenchyma: the endothelin-A receptor is found mainly in the
vascular compartment, and the endothelin-B receptor is found mainly in the
tubular compartment. In an animal model of glycerol-mediated toxic renal injury,
selective antagonism of the endothelin-A receptor lessened the reduction in glomerular
filtration rate [18]. Preliminary evidence suggested that the endothelin-B
receptor was integral to clearing endothelin-1, and probably plays a beneficial
role in ischemia. Studies of selective endothelin-A receptor blockade and
nonselective endothelin receptor blockade (both endothelin-A receptor and
endothelin-B receptor) demonstrated improved outcomes only for the selective
blockade in a chronic ischemia animal model, further supporting the beneficial
effects of intact endothelin-B receptor function [19].
Tumor necrosis factor and interleukin-1
Major mediators of cytokine-induced renal injury include TNF and IL-1, both
of which promote further cytokine release, induce vasoconstriction, neutrophil
aggregation, production of reactive oxygen species, and induction of tissue
factor and promotion of thrombosis [20]. When infused into animal models, TNF
and IL-1 result in renal damage and decrease RBF and glomerular filtration rate
[21]. TNF is produced and circulated systemically, whereas IL-1 is expressed in
the glomerular endothelial cells early in animal models of sepsis. These pleiotropic
cytokines are capable of inducing mesangial and endothelial production
of PAF, endothelin, adenosine, NO, and prostaglandin E 2 . The migration of
activated neutrophils into the kidney in the setting of up-regulation of adhesion
molecule expression by activated endothelial cells leads to further endothelial
damage and is likely a seminal event in the pathogenesis of ARF. Ischemic
animal models of ARF demonstrate a protective effect of monoclonal antibodies
to adhesion molecules [22].

216
klenzak & himmelfarb
Local soluble mediators
Cellular and humoral cytokines are integral to organ dysfunction in sepsis
syndromes, with the kidney being especially vulnerable to cytokine-mediated
injury. CD14 is expressed by mesangial cells and can be stimulated directly by
LPS. The mesangial cells are capable of expressing multiple proinflammatory
cytokines and chemokines, IL-1, IL-6, TNF, and PAF. Tubular cells are also
capable of releasing proinflammatory cytokines after stimulation by LPS [23].
Studies of isolated kidneys perfused ex vivo with LPS do not demonstrate
a decrease in glomerular filtration rate despite increased mRNA expression for
proinflammatory cytokines. In vivo experiments involving LPS stimulation
demonstrate the expected renal dysfunction, however, suggesting that the ARF in
this setting is caused by host factors outside the renal parenchyma [24,25].
Specific mediators of vascular resistance and endothelial injury whose expression
is induced by LPS in vivo include PAF, endothelin-1, and iNOS. Each of these
soluble proteins has been shown to decrease glomerular filtration rate and RBF,
leading to decreased urine output. Animal studies using antagonists to each of
these soluble mediators have demonstrated amelioration of the renal injury
[15,19,26].
PAF is a vasoconstrictor that additionally is chemotactic for activated
inflammatory cells, including neutrophils. It can be produced by glomerular
cells and by circulating inflammatory cells, such as neutrophils and macrophages.
Increases in PAF lead to a reduction in glomerular filtration rate. Blockade of
PAF receptors lessens the deterioration of renal function in models of endotoxemia
[26].
Oxidative stress
It has recently been demonstrated that there are high levels of oxidative stress
in patients with ARF in the setting of critical illness. These patients demonstrated
diminished thiol content and increased carbonyl content in plasma proteins. The
excess burden of protein oxidation is significantly greater in patients with ARF as
compared with critically ill patients with preserved renal function or patients with
dialysis-dependent chronic kidney disease. The levels of protein oxidation are
improved by dialysis, but only transiently, and oxidized proteins continue to
accumulate during the intradialytic period [27]. The oxidative burden in patients
who have ARF in the setting of critical illness may be a target for potential
therapies to decrease their excess mortality.
Endothelium
Endothelial activation induced by circulating cytokines and activated complement
is likely a key instigator in the evolution of sepsis-associated ARF.
The changes induced in endothelial function by this stimulation enhance the

inflammatory process by increasing the production of inflammatory mediators.
Endothelial activation is an early host response to circulating pathogens, and
likely is triggered by activated and adherent neutrophils and their degradation
products. The release of cytokines from the activated endothelium may be an
early and aggressive defense. The dysfunctional endothelium is more severely
damaged and results in the leaky capillaries associated with sepsis. The process
by which endothelium evolves from activated and physiologic to damaged and
dysfunctional is relatively unknown and represents a key area for research and a
potential target for therapy.
Coagulation cascade
sepsis and the kidney 217
The activation of coagulation and deposition of fibrin in the tissues is a welldefined
component of the MOSF in sepsis. Increased expression of tissue factor
in response to LPS and TNF stimulation of inflammatory and endothelial cells
may contribute to organ injury in sepsis, including renal injury. Tissue factor
binds activated factor VII. This complex activates factor X, which cleaves
prothrombin to thrombin, which in turn cleaves fibrinogen to fibrin. The activation
of the coagulation cascade increases the tissue inflammatory response. Fibrin
is often deposited in the intravascular space in animal models of sepsis, including
the glomerular capillaries. For these reasons, anticoagulant therapies, or therapies
that interfere with initiation of coagulation, are of potential interest in ameliorating
MOSF, including renal failure. In a primate model of sepsis, animals were
treated with site-inactivated factor VIIa, which serves as a competitive inhibitor
of tissue factor, to block the initiation of the coagulation cascade. The treated
animals showed preserved renal function at 48 hours, less metabolic acidosis, and
better urine output. Histologic examination of the kidneys demonstrated less
tubular injury, inflammatory cell infiltration, and fewer fibrin clots than in untreated
animals [28]. Activated protein C improves outcomes in sepsis, and it is
currently unclear whether it also attenuates sepsis-associated ARF [29].
Management of sepsis-associated acute renal failure
Renal replacement therapy
The introduction of hemodialysis for the treatment of severe ARF lowered the
mortality rate from greater than 90% to approximately 50%. The widespread
availability of continuous renal replacement therapies (CRRT) has led to a
growing interest in its use for the possible removal of proinflammatory cytokines
in sepsis, in addition to its use in volume and urea clearance. The use of CRRT
is favored in patients with pressor-dependence because of its better hemodynamic
tolerability than intermittent hemodialysis. Additionally, CRRT offers
potentially improved adequacy through clearance of solute. After intermittent

218
klenzak & himmelfarb
hemodialysis, there is a rebound effect on solutes that are intracellular or otherwise
sequestered. The continuous aspect of CRRT allows for a more physiologic
and consistent clearance, without rebound effects. Delivered dose of RRT may
have an impact on survival. In a study of three dose levels, indicated by differing
filtration rates, a survival benefit was demonstrated for patients receiving
the most ultrafiltration by continuous venovenous hemofiltration (CVVH).
This study compared prescribed doses of 20, 35, and 45 mL/h/kg. The survival
rates were 41%, 57%, and 58%, respectively. In this study, patients with sepsis
demonstrated more survival benefit than other critically ill patients with the
increase in dialysis dose from 35 to 45 mL/h/kg [30].
This finding increased interest in using high-volume hemofiltration, or
ultrafiltration beyond 3000 mL/h, in the treatment of sepsis-associated ARF.
Animal models demonstrated survival and hemodynamic benefits for highvolume
hemofiltration in endotoxemia. Furthermore, increases in ultrafiltration
rate increase convective clearance, and increase clearance of middle molecules,
which include most soluble mediators of sepsis. Controlled trials in patients have
failed, however, to demonstrate a significant clearance of soluble cytokines in
RRT. Specifically, a randomized controlled trial of patients with sepsis and
preserved renal function allocated to either CVVH at 2 L/h or no hemofiltration
demonstrated no difference in circulating cytokines or anaphylatoxins. CVVH
in this setting did not improve clinical indicators, such as oxygenation, or the
duration of pressor support [31]. Additionally, a study of patients with sepsisassociated
ARF undergoing CVVH demonstrated no changes in circulating IL-6
or TNF levels. There was clearance of IL-6, demonstrated by its presence in the
ultrafiltrate, but the plasma levels remained stable [32].
To pursue middle molecule clearance, high-permeability membranes were developed
to provide better diffusive clearance for soluble mediators of inflammation
through increased pore size. The inflammatory dysregulation in systemic
inflammatory response syndrome is characterized by a decreased proliferative
capacity and hyporesponsiveness of peripheral blood mononuclear cells. Studies
of patients with sepsis-associated ARF have demonstrated an improvement in
these circulating cells’ ability to respond ex vivo to stimuli after treatment with
high-flux CRRT. Studies comparing high-flux with conventional CRRT have
demonstrated restoration of the normal responsiveness to stimulation with anti-
CD3 antibodies or endotoxin [33,34]. Morgera et al [33] additionally incubated
peripheral blood mononuclear cells from healthy volunteers with the ultrafiltrate
of septic patients and demonstrated the hyporesponsiveness characteristic of
MOSF. There is likely a circulating suppressor of monocyte function.
Plasmapheresis and adsorption
Concurrent with interest in high-dose CRRT, it was postulated that normal
inflammatory and anti-inflammatory balance could be restored with the use of
other blood purification techniques, including plasmapheresis or plasma exchange,
or adsorption techniques, in addition to RRT. A pilot study of adjunctive

treatment of 25 patients with plasma exchange in the setting of sepsis-associated
MOSF, including renal failure, demonstrated a survival of 80%, higher than is
expected [35]. Other studies have shown survival rates of 0% to 100%. A larger
trial that included 106 patients randomized to receive plasma exchange or
conventional treatment showed a mortality rate of 33.3% in the treated group
versus 53.8% in the control group (P = .04). This study only included 19 patients
who developed MOSF, however, 13 of whom were randomized to the control
group [36]. Theoretically, not only the removal of the dysregulated cytokines and
anaphylatoxins, including endotoxin, TNF, IL-6, IL-10, and PAI, but also the
removal of cellular debris, lysosomal enzymes, proteases, activated complement,
and coagulation components, could be beneficial. Additionally, in plasma exchange,
the reconstitution with healthy plasma components may also help restore
the normal balance between proinflammatory and anti-inflammatory cytokines.
A more selective approach to the removal of harmful solutes in the plasma is
the use of adsorbent technology. In this type of purification, the plasma is filtered
through a column containing polymyxin B beads, which preferentially bind
toxins and have been shown to decrease plasma levels of TNF. In a prospective
pilot trial of 10 patients randomized to either 10 hours of plasma filtration
adsorption with hemodialysis or continuous venovenous hemodiafiltration
(CVVHDF), the investigators found that adsorption therapy increased monocyte
responsiveness, as measured by LPS stimulation [37].
Bioartificial kidney
sepsis and the kidney 219
A newer RRT being developed is the renal tubule-assist device. In animal
models of septic shock, Fissell et al [38] demonstrated superior hemodynamics,
cytokine profiles, and outcomes using the bioartificial kidney, which is
hemofiltration in series with the renal tubule-assist device. The renal tubule-assist
device is created by growing porcine renal tubular cells in confluent monolayers
along the inner surface of the fibers in a standard hemofiltration cartridge. In
theory, replacement of dialytic clearance with metabolically active tubular cells
may provide a more physiologic metabolic milieu, possibly attenuating the
course of MOSF. In an animal model of sepsis-associated ARF, which consisted
of dogs with bilateral nephrectomies followed by intraperitoneal administration
of Escherichia coli, the animals received either renal tubule-assist device therapy,
or a sham renal tubule-assist device treatment (blood was hemofiltered, but
without the tubular cell column). The renal tubule-assist device–treated dogs
survived significantly longer and demonstrated improved hemodynamics. They
had significantly higher TNF and IL-10 plasma levels, and better electrolyte
homeostasis. The investigators also measured 1,25-(OH) 2 vitamin D 3 levels, and
found that the sham renal tubule-assist device–treated dogs continued to show
decline in plasma levels, whereas the renal tubule-assist device–treated group
stabilized to pretreatment levels, demonstrating this metabolic activity in the renal
tubule-assist device column [38]. In another experimental model, the dogs were
nephrectomized, stabilized on CRRT with renal tubule-assist device or without

220
klenzak & himmelfarb
renal tubule-assist device, and then infused with endotoxin. Again, IL-10 levels
were higher in the renal tubule-assist device–treated group, as was mean arterial
pressure. Survival data were not published [39]. To assess whether the renal
tubule-assist device ameliorates the course of sepsis before renal failure, the
investigators assessed it in pigs administered E. coli intraperitoneally, which were
immediately started on CVVHF with or without renal tubule-assist device. All of
the animals developed ARF within hours. This study demonstrated a significant
increase in survival time, associated with better systemic hemodynamic
measurements and renal artery blood flow. IL-6 and interferon-g levels were
lower in renal tubule-assist device–treated animals, but most cytokines measured
did not demonstrate significant differences between renal tubule-assist device and
sham-treated animals [40].
Summary
When renal failure occurs, the systemic and local dysregulation of sepsis is
compounded by loss of metabolic, fluid, and electrolyte homeostasis. The loss of
renal function increases mortality, and those who do survive likely do so with the
return of renal function. The interplay between systemic host responses and local
injury and activity in the kidney affects the vascular bed, the immune system, and
plays a role in the development of MOSF. Patients with end-stage renal disease
and sepsis have a lower mortality rate than those who develop ARF in the setting
of sepsis. Despite advances in RRT and critical care, mortality rates have
remained fairly stable over the last two decades for sepsis-associated ARF. There
is little conclusive evidence from human trials of great benefit from the myriad of
original therapies tested to date.
For these reasons, it is important to learn more about the human response to
sepsis and ARF, and to clarify the differences between patients who develop renal
failure and those who do not; and to clarify the differences between those who
survive, and those who do not. It is these variables, in the ICU, which may serve
to aid in designing rational therapies for the restoration of metabolic balance and
the return of renal function.
References
[1] Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory
response syndrome (SIRS): a prospective study. JAMA 1995;273:117–23.
[2] Clermont G, Acker CG, Angus DC, et al. Renal failure in the ICU: comparison of the impact
of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int 2002;62:986–96.
[3] Lugon JR, Boim MA, Ramos OL, et al. Renal function and glomerular hemodynamics in
male endotoxemic rats. Kidney Int 1989;36:570–5.
[4] Kashgarian M, Siegel NJ, Ries AL, et al. Hemodynamic aspects in development and recovery
phases of experimental postischemic acute renal failure. Kidney Int Suppl 1976;6:S160–8.

sepsis and the kidney 221
[5] Mason J, Torhorst J, Welsch J. Role of the medullary perfusion defect in the pathogenesis
of ischemic renal failure. Kidney Int 1984;26:283–93.
[6] Wan L, Bellomo R, Di GD, et al. The pathogenesis of septic acute renal failure. Curr Opin Crit
Care 2003;9:496–502.
[7] Schaer GL, Fink MP, Parrillo JE. Norepinephrine alone versus norepinephrine plus low-dose
dopamine: enhanced renal blood flow with combination pressor therapy. Crit Care Med 1985;
13:492–6.
[8] Anderson WP, Korner PI, Selig SE. Mechanisms involved in the renal responses to intravenous
and renal artery infusions of noradrenaline in conscious dogs. J Physiol 1981;32:121–30.
[9] Korner PI, Stokes GS, White SW, et al. Role of the autonomic nervous system in the renal
vasoconstriction response to hemorrhage in the rabbit. Circ Res 1967;20:676–85.
[10] Zhang H, Smail N, Cabral A, et al. Effects of norepinephrine on regional blood flow and oxygen
extraction capabilities during endotoxic shock. Am J Respir Crit Care Med 1997;155:1965 –71.
[11] Bersten AD, Rutten AJ. Renovascular interaction of epinephrine, dopamine, and intraperitoneal
sepsis. Crit Care Med 1995;23:537– 44.
[12] Bersten AD, Rutten AJ, Summersides G, et al. Epinephrine infusion in sheep: systemic and renal
hemodynamic effects. Crit Care Med 1994;22:994–1001.
[13] Di GD, Morimatsu H, May CN, et al. Intrarenal blood flow distribution in hyperdynamic
septic shock: effect of norepinephrine. Crit Care Med 2003;31:2509–13.
[14] Cohen RI, Hassell AM, Marzouk K, et al. Renal effects of nitric oxide in endotoxemia.
Am J Respir Crit Care Med 2001;164(10 Pt 1):1890–5.
[15] Spain DA, Wilson MA, Garrison RN. Nitric oxide synthase inhibition exacerbates sepsisinduced
renal hypoperfusion. Surgery 1994;116:322–30.
[16] Knotek M, Esson M, Gengaro P, et al. Desensitization of soluble guanylate cyclase in renal
cortex during endotoxemia in mice. J Am Soc Nephrol 2000;11:2133–7.
[17] Zimmerman GA, Prescott SM, McIntyre TM. Endothelial cell interactions with granulocytes:
tethering and signaling molecules. Immunol Today 1992;13:93 – 100.
[18] Shimizu T, Kuroda T, Ikeda M, et al. Potential contribution of endothelin to renal abnormalities
in glycerol-induced acute renal failure in rats. J Pharmacol Exp Ther 1998;286:977–83.
[19] Forbes JM, Hewitson TD, Becker GJ, et al. Simultaneous blockade of endothelin A and B
receptors in ischemic acute renal failure is detrimental to long-term kidney function. Kidney Int
2001;59:1333– 41.
[20] Thijs A, Thijs LG. Pathogenesis of renal failure in sepsis. Kidney Int Suppl 1998;66:S34–7.
[21] Kohan DE. Role of endothelin and tumour necrosis factor in the renal response to sepsis.
Nephrol Dial Transplant 1994;9(Suppl 4):73–7.
[22] Linas SL, Whittenburg D, Parsons PE, et al. Ischemia increases neutrophil retention and worsens
acute renal failure: role of oxygen metabolites and ICAM 1. Kidney Int 1995;48:1584–91.
[23] Camussi G, Ronco C, Montrucchio G, et al. Role of soluble mediators in sepsis and renal failure.
Kidney Int Suppl 1998;66:S38– 42.
[24] Xia Y, Feng L, Yoshimura T, et al. LPS-induced MCP-1, IL-1 beta, and TNF-alpha mRNA
expression in isolated erythrocyte-perfused rat kidney. Am J Physiol 1993;264(5 Pt 2):F774–80.
[25] Linas SL, Whittenburg D, Repine JE. Role of neutrophil derived oxidants and elastase in
lipopolysaccharide-mediated renal injury. Kidney Int 1991;39:618–23.
[26] Wang J, Dunn MJ. Platelet-activating factor mediates endotoxin-induced acute renal
insufficiency in rats. Am J Physiol 1987;253(6 Pt 2):F1283–9.
[27] Himmelfarb J, McMonagle E, Freedman S, et al. Oxidative stress is increased in critically ill
patients with acute renal failure. J Am Soc Nephrol 2004;15:2449–56.
[28] 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 – 9.
[29] Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated
protein C for severe sepsis. N Engl J Med 2001;344:699–709.
[30] Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous
haemofiltration on outcomes of acute renal failure: a prospective randomised trial. Lancet 2000;
356:26–30.

222
klenzak & himmelfarb
[31] Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous
hemofiltration in sepsis. Crit Care Med 2002;30:100– 6.
[32] Klouche K, Cavadore P, Portales P, et al. Continuous veno-venous hemofiltration improves
hemodynamics in septic shock with acute renal failure without modifying TNF-alpha and IL-6
plasma concentrations. J Nephrol 2002;15:150–7.
[33] Morgera S, Haase M, Rocktaschel J, et al. High permeability haemofiltration improves peripheral
blood mononuclear cell proliferation in septic patients with acute renal failure. Nephrol Dial
Transplant 2003;18:2570–6.
[34] Lonnemann G, Bechstein M, Linnenweber S, et al. Tumor necrosis factor-alpha during
continuous high-flux hemodialysis in sepsis with acute renal failure. Kidney Int Suppl 1999;
72:S84–7.
[35] Stegmayr BG. Plasma exchange in patients with septic shock including acute renal failure.
Blood Purif 1996;14:102–8.
[36] Busund R, Koukline V, Utrobin U, et al. Plasmapheresis in severe sepsis and septic shock:
a prospective, randomised, controlled trial. Intensive Care Med 2002;28:1434–9.
[37] Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration with
adsorption in septic shock. Crit Care Med 2002;30:1250–5.
[38] Fissell WH, Lou L, Abrishami S, et al. Bioartificial kidney ameliorates gram-negative bacteriainduced
septic shock in uremic animals. J Am Soc Nephrol 2003;14:454–61.
[39] Fissell WH, Dyke DB, Weitzel WF, et al. Bioartificial kidney alters cytokine response and
hemodynamics in endotoxin-challenged uremic animals. Blood Purif 2002;20:55– 60.
[40] Humes HD, Buffington DA, Lou L, et al. Cell therapy with a tissue-engineered kidney reduces
the multiple-organ consequences of septic shock. Crit Care Med 2003;31:2421– 8.