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

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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

O2

TUBULAR
Cytoskeletal breakdown Loss of polarity

Inflammatory Apoptosis and Necrosis and Desquamation of viable vasoactive and necrotic cells mediators Tubular obstruction Backleak

Fig. 1. Pathophysiology of ischemic acute renal failure. PGE2, prostaglandin E2.

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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

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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 [712]. 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

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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 A2 by the endothelium. Additionally, endothelin induces some vasodilators, counteracting its vasoconstricting effect, including prostacyclin, NO, and prostaglandin E2. 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 E2. 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].

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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

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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 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

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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 antiCD3 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

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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 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 devicetreated 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 D3 levels, and found that the sham renal tubule-assist devicetreated dogs continued to show decline in plasma levels, whereas the renal tubule-assist devicetreated 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

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renal tubule-assist device, and then infused with endotoxin. Again, IL-10 levels were higher in the renal tubule-assist devicetreated 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 devicetreated 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.

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