M. Raghavan, R. Venkataraman, and J.A. Kellum
Introduction
Acute renal failure remains a common syndrome in the setting of critical illness, and is associated with a high risk of death. Approximately 1–25% of patients in the intensive care unit (ICU) develop acute renal failure depending on the criteria used to define its presence [1]. Severe sepsis plays a major factor in the development of acute renal failure in the ICU. The mortality from sepsis-induced acute renal failure remains high despite our increasing ability to support vital organs. Unfortunately our understanding of the pathogenesis of sepsis-induced renal dysfunction is quite limited. It is, therefore, very important for critical care physicians to have an appreciation of what is known and not known about this condition in order to implement rational therapies.
Epidemiology of Sepsis-induced Acute Renal Failure in the ICU
Sepsis and severe sepsis are currently the major contributing factors in the evo- lution of acute renal failure in ICU patients and account for nearly 50% of acute renal failure observed in the ICU [2]. Acute renal failure occurs in approximately 19% of patients with moderate sepsis, 23% with severe sepsis, and 51% with septic shock when blood cultures are positive [3]. Despite considerable improvements in medical treatment of various critical illnesses over the last three decades, the ther- apy of acute renal failure is rather disappointing and mortality rates due to acute renal failure exceed 60% in many published series [2]. It remains unclear, however, whether acute renal failure plays a significant role in the subsequent development of multiple organ failure (MOF) through its effects on metabolic homeostasis, or if acute renal failure is merely a manifestation of MOF. Patients who develop acute renal failure in the setting of sepsis are more likely to die than dialysis-dependent patients with sepsis admitted to the ICU [4]. This suggests that new onset acute renal failure during critical illness by itself has an ‘attributable’ mortality, and that the poor outcome associated with the development of new onset renal dysfunction is independent of the poor outcome associated with sepsis syndrome [5].
Pathophysiology of Sepsis-induced Acute Renal failure:
‘Time for a Paradigm Shift’
In the past, acute renal failure during critical illness was essentially considered a ‘hemodynamic disease’ caused by renal ischemia, a view largely influenced by findings in animal models, at least some of which had questionable relevance to the clinical state. Indeed, most models inducing so-called acute tubular necrosis (ATN) are based on ischemia/reperfusion (e. g., renal artery clamping). Such mod- els produce very different physiology compared to the high cardiac output, low systemic vascular resistance state typically seen during human sepsis. Recent re- search however, underscores the importance of other mechanisms of renal injury such as acute renal tubular cell apoptosis [6,7], renal tubular epithelial barrier dys- function [8], and endothelial dysfunction [9] in the pathogenesis of sepsis-induced acute renal failure. These concepts fit well with the typical paucity of histologic findings seen in ATN and with growing evidence of varying mechanisms of organ injury during sepsis and inflammation in general [8, 10]. Thus, the pathophysio- logic mechanisms whereby sepsis-induced acute renal failure occur can be divided into four broad areas: 1. renal perfusion; 2. inflammation; 3. cellular mechanisms;
and 4. coagulation.
Renal Perfusion
The concept of renal hypoperfusion as the primary cause of acute renal failure is so thoroughly engrained in the literature of critical care and nephrology as to elevate to the status of dogma. Even the terms that we use, (e. g. acute tubular necrosis) suggest an ischemic etiology. For many years, empiric treatment of renal hypoperfusion with dopamine, a renal vasodilator, was seen as standard care not only for patients with acute renal failure but even for patients thought to be at high risk of acute renal failure. This practice has largely ceased after evidence accrued that dopamine is not helpful [11, 12] but other vasodilators (e. g., fenoldopam) are still being investigated. Furthermore, many clinicians shun agents such as norepinephrine over concerns that renal vasoconstriction will result in further deterioration in renal function. In this context, it is perhaps important to recall that blood flow to the kidneys is normally many times greater than metabolic need.
This is because total or ‘global’ renal blood flow is in the service of glomerular filtration rather than oxygen delivery.
Global Renal Blood Flow
Traditionally, the observation of an association between acute renal failure and
‘low flow’ states, such as cardiogenic, hemorrhagic, or even septic shock, led to the belief that renal ischemia plays a key role in the evolution of acute renal failure.
This construct implies that restoration and maintenance of adequate renal blood
flow should therefore be the primary target for renal protection in the critically ill.
Several experimental studies of sepsis-induced acute renal failure have shown that global renal blood flow declines after induction of sepsis or endotoxemia [3,13,14].
Current evidence, however, suggests that most of sepsis-induced acute renal failure arises not due to renal hypoperfusion but indeed in the setting of adequate, or even increased renal perfusion [15]. Therefore, while renal hypoperfusion might be important in ‘low flow’ shock states, it is unlikely to play a key role in the development of acute renal failure during hyperdynamic states such as sepsis. The observation of acute renal failure in hyperdynamic models of septic shock suggests that renal blood flow-independent mechanisms of renal injury must exist and may be more important in the pathogenesis of sepsis-induced acute renal failure.
Intrarenal Hemodynamics
It is possible that even though there is preserved or increased global renal blood flow during sepsis, regional redistribution of blood flow favoring the cortex, so- called ‘cortico-medullary redistribution’, may occur [16]. However recent studies by Di Giantomasso and colleagues found that both cortical and medullary blood flows remain unchanged in sheep with hyperdynamic septic shock, conditions closely resembling those of clinical sepsis [17]. Interestingly, the administration of norepinephrine resulted in a significant increase in flow to both regions. These observations challenge the view that the medulla is ischemic during hyperdynamic sepsis but simultaneously highlight that hemodynamic factors are indeed at work, and can be modified by interventions that affect systemic blood pressure and cardiac output. Furthermore, although cortico-medullary redistribution could be an important mechanism of renal injury in certain settings, it is likely to repre- sent only one of the potential mechanisms responsible for loss of renal function.
Although these studies do not completely discount the possible role of regional hypoperfusion (particularly in the microcirculation) in the pathophysiology of sepsis-induced acute renal failure, they do suggest that other factors, such as me- diators of cellular injury, rather than lack of blood flow, may be closer to center stage in this unfolding drama [6].
Inflammation
Since neither global renal hemodynamic changes nor intrarenal hemodynamic changes have been consistently shown to be predominant contributors to sepsis- induced acute renal failure, there must, therefore, be other mechanisms at work during the evolution of sepsis-induced acute renal failure that are not hemody- namic in nature. Sepsis is characterized by the release of a vast array of inflam- matory cytokines, arachidonate metabolites, vasoactive substances, thrombogenic agents, and other biologically active mediators. A large body of experimental data
suggests that these various mediators, along with neuroendocrine mechanisms, might be involved in the pathogenesis of organ dysfunction in sepsis [10].
Cytokines
Cellular and humoral factors are integral to organ dysfunction in sepsis syndrome, with the kidney being especially vulnerable to cytokine-mediated injury. The mesangial cells are capable of expressing multiple pro-inflammatory cytokines and chemokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF), and platelet activating factor (PAF) (Fig. 1). Tubular cells are also capable of releasing pro-inflammatory cytokines after stimulation by lipopolysaccharide (LPS) [18].
Studies of isolated kidneys perfused ex vivo with LPS do not demonstrate a decrease in glomerular filtration rate (GFR) despite increased mRNA expression for pro- inflammatory cytokines. However, in vivo experiments involving LPS stimulation demonstrate the expected renal dysfunction, suggesting that the acute renal failure in this setting involves host factors outside the renal parenchyma [19, 20].
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 (ROS), and induction of tissue factor and promotion of thrombosis [21]. TNF is produced and circulated system- ically, whereas IL-1 is expressed in the glomerular endothelial cells early in animal models of sepsis. In the kidney, endotoxin also stimulates release of TNF from glomerular mesangial cells [22]. When infused into animal models, TNF and IL-1 result in renal damage and decreased renal blood flow and GFR [23]. Messmer et al. [24] have shown that TNF and LPS elicit apoptotic cell death of cultured bovine glomerular endothelial cells, which is time and concentration dependent. The effect of these compounds was characterized by an increase in proapoptotic proteins and a decrease in antiapoptotic proteins such as Bcl-xL. Furthermore, these pleiotropic cytokines are capable of inducing mesangial and endothelial production of PAF, endothelin, adenosine, nitric oxide (NO), and prostaglandin E2.
More recently, the direct toxic role of TNF to the kidney has been become evi- dent. Knotek et al. [25] using soluble TNF receptor 55 (TNFsRp55)-based neutral- ization of TNF, achieved protection against LPS-induced renal failure in wild-type mice. With pretreatment using TNFsRp55, GFR decreased by only 30%, compared with a 75% decrease without TNF neutralization, suggesting that TNF plays an important role in sepsis-induced acute renal failure. Furthermore, van Lanschot et al. [26] infused TNF in sublethal doses in dogs. TNF induced an increase in water and sodium excretion, an effect that could be prevented by prior cyclooxygenase inhibition, suggesting that vasodilatory prostaglandins mediated some of the renal response to sublethal TNF in this model. Cunningham and colleagues [27] used Escherichia coli LPS as an intraperitoneal injection to establish a mice model of sepsis, and showed that LPS-induced acute renal failure can be attributed to TNF acting directly on its receptor, TNF Receptor-1 (TNFR1), in the kidney. Mice defi- cient in TNF receptor were resistant to LPS-induced renal failure, had less tubular
Fig. 1. Pathophysiology of acute renal failure and recovery during sepsis. Sepsis induces renal injury by a variety of mechanisms. Injured cells may recover promptly or undergo apoptosis or, rarely, necrosis. They may undergo de-differentiation and proliferation to replace lost cells.
Control over these processes is complex and involves numerous factors. RTC: renal tubular cells;
TNF: tumor necrosis factor; IL: interleukin; PAF: platelet activating factor; RBF: renal blood flow
apoptosis, and had fewer infiltrating neutrophils. Although TNF receptor-negative mice implanted with TNF receptor-positive kidneys developed LPS-induced renal failure, TNF-positive mice implanted with TNF receptor-negative kidneys did not.
TNF thus seems to be an important direct mediator of endotoxin’s effects during sepsis-induced acute renal failure. However, despite all the above findings, TNF blockade with monoclonal antibodies fails to protect animal or kidney during en- dotoxemia [28]. These observations suggest that toxic/immunologic mechanisms are important in mediating renal injury during sepsis.
Nitric Oxide
During hyperdynamic septic shock renal blood flow 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 NO in the medulla [29]. Inducible NO synthase (iNOS) can be expressed locally,
in glomerular mesangial cells and endothelial cells, after stimulation with pro- inflammatory cytokines, including TNF and IL-1, and endotoxin [30]. Nonselective or selective blockade of iNOS decreases renal blood flow while increasing mean arterial pressure (MAP). This suggests that iNOS plays a role in maintaining renal blood flow in the setting of shock through its vasodilatory effects at the afferent arteriole. The mechanism of vasodilation by NO is dependent on the synthesis of cyclic guanosine monophosphate (cGMP) by soluble guanylate cyclase. Studies of LPS stimulation in mice leading to shock and acute renal failure have demonstrated a decrease in cGMP 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 [31]. NOS inhibition in animal models of endotoxemia results in glomerular thrombosis and decline in creatinine clearance. The glomerular thrombosis in the setting of NOS inhibition seems related to the antithrombotic qualities of NOS, by inhibiting leukocyte interactions with endothelial cells and inhibiting platelet aggregation [32].
Endothelins
The production of endothelins, which are potent vasoconstrictors, by endothe- lial, mesangial, and tubular cells is stimulated by pro-inflammatory cytokines, including TNF. The vasoconstrictors, vasopressin and angiotensin II, also stimu- late 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 PAF synthesis in the mesangium or thromboxane A2 by the endothelium. PAF is a vasoconstrictor that additionally is chemotactic for activated inflammatory cells, including neutrophils. Increases in PAF lead to a reduction in GFR. Blockade of PAF receptors lessens the deterioration of renal function in animal models of endotoxemia [33].
Additionally, endothelin also induces some vasodilators, counteracting its vasoconstricting effect, including prostacyclin, NO, and prostaglandin E2. Two en- dothelin 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 reduc- tion in GFR [34]. Preliminary evidence suggested that the endothelin-B receptor is 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) demon- strated improved outcomes only for the selective blockade in a chronic ischemia animal model, further supporting the beneficial effects of intact endothelin-B receptor function [35].
Oxidative Stress
Endotoxemia is known to be associated with the generation of reactive oxygen radicals and thus may contribute to oxidative renal injury [3, 36, 37]. Endogenous
scavengers of ROS have been shown to attenuate renal tubular injury during en- dotoxemia. During endotoxemia, levels of endogenous scavengers of ROS such as extracellular superoxide dismutase, which is found predominantly in blood ves- sels and the kidney, have been noted to be decreased [36]. In a murine model of septic shock and acute renal failure, administration of a superoxide dismu- tase mimetic that had properties of oxygen-radical scavengers decreased deaths in the animals [36]. Oxygen radicals also scavenge NO to produce peroxynitrite, an injurious ROS. This excess burden of protein oxidation is significantly greater in patients with acute renal failure as compared with critically ill patients with preserved renal function. The levels of protein oxidation are improved by dialy- sis, but only transiently, and oxidized proteins continue to accumulate during the intradialytic period [37]. The oxidative burden in patients who have acute renal failure in the setting of critical illness may be a target for potential therapies to decrease the excess mortality in these patients.
Cellular Mechanisms
Epithelial Dysfunction
The clinical syndrome of acute renal failure in the setting of sepsis manifests itself by a decreasing urine output and rising serum creatinine. It is highly improbable that loss of cell mass per se (either by necrosis or apoptosis) accounts for the de- velopment of renal dysfunction. Since the histopathology of acute renal failure in humans is remarkably bland, the final step in the development of acute renal failure is probably the widespread dysfunction of renal tubular epithelial cells as a result of the deleterious effects of a poorly controlled sepsis-induced inflammatory re- sponse [8]. An important step in this process is the dysfunction of specialized structures in tubular epithelial cells namely the tight junctions [38]. During the evolution of sepsis-induced acute renal failure, dysfunction of tight junctions leads to backleakage of tubular fluid across the epithelium [8, 39]. Loss of cell adhesion to the tubular basement membrane and subsequent shedding into the lumen re- sults in denuded cells appearing in the urine as tubular epithelial cell casts. 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 energy consuming metabolic activity. All of the above mechanisms collectively induce re- nal dysfunction in the absence of overt histological features of renal tubular cell loss.
The Endothelium
Endothelial activation induced by circulating cytokines and activated complement is likely a key instigator in the evolution of sepsis-induced acute renal failure.
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 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.
Apoptosis
Cells can die by one of two pathways: necrosis or apoptosis. Apoptosis is an energy- requiring form of cell death that is mediated by a genetically determined bio- chemical pathway and is characterized morphologically by cell shrinkage, plasma membrane blebbing, chromatin condensation, and nuclear fragmentation [6,7,40].
Necrosis, however, results from severe ATP depletion and leads to uncoordinated and rapid collapse of cellular homeostasis. Because apoptosis does not result in the release of intracellular material into the extracellular space, it does not result in an inflammatory response [7]. Apoptotic cells are present in tissue sections for a very short period of time (1±3 hours) before being phagocytosed and destroyed.
By contrast, it may take days for histologic evidence of cell necrosis to resolve.
Therefore, counting the number of apoptotic and necrotic cells in tissue sections is likely to substantially underestimate the contribution of apoptosis to cell death [7].
Current evidence suggest that human renal tubular cells die by apoptosis as well as necrosis in patients with acute renal failure [41]. Apoptosis is more commonly seen in distal tubular cells, both in animals and in allografts of patients with biopsy-confirmed ATN [42]. It is not yet possible, however, to quantify the relative contributions made by necrosis and apoptosis during acute renal failure in vivo.
Schumer et al. [43] have demonstrated that after a very brief period of is- chemia (5 minutes), apoptotic bodies could be found 24 hours and 48 hours after reperfusion, and without any evidence of necrosis. After more prolonged periods of ischemia, areas of necrosis became evident, but substantial numbers of apop- totic bodies were still seen after 24 to 48 hours of reperfusion. Until recently the mode of cell necrosis following ischemia was thought to be entirely related to the severity of ATP depletion [40]. Dagher and colleagues [44] however, have shown that ischemia causes depletion of ATP as well as guanine triphosphate (GTP) in cultured renal tubular cells and in the ischemic kidney in vivo. Using selective depletion techniques of either ATP or GTP these authors showed that isolated ATP depletion induces necrosis and GTP depletion induces apoptosis. Although GTP supplementation has been shown to reduce apoptosis and ameliorate ischemic renal dysfunction, the mechanisms responsible for the differences in the mode of cell death induced by ATP and GTP depletion remains to be elucidated [45]. The evidence of whether apoptosis plays an important role in tubular injury in vivo remains controversial. Particularly controversial is whether renal cell apoptosis occurs in any large measure during sepsis.
‘Death Receptors’
The most extensively characterized ‘death receptors’ belong to the TNF receptor family and include CD95 (Fas) and TNFR-1 [46]. The intracellular domains of these receptors contain ‘death domains’. The binding of Fas ligand (FasL) and TNF to their respective receptors, Fas and TNFR-1, leads to oligomerization of the receptors and subsequent activation of caspase 8. While renal tubular cells con- stitutively express Fas and TNFR-1 [47, 48], they are normally relatively resistant to FasL- and TNF-induced apoptosis. However, during sepsis and endotoxemia renal tubular cells are exposed to inflammatory cytokines or to ATP depletion (which induces cytokine release from these cells) [49], the expression of Fas/FasL and TNF-α/TNFR-1 is upregulated, and the cells become sensitized to Fas and TNF mediated apoptosis [48]. Jo et al. [50] have recently shown that apoptosis of tubular cells by inflammatory cytokines and LPS is a possible mechanism of renal dysfunction in endotoxemia. They found that if high-dose TNF was added to cul- tured kidney proximal tubular cells, there was increased expression of Fas mRNA, the Fas associated death domain protein, as well as increased DNA fragmentation.
These findings suggest that constitutively expressed death receptors, FasL and TNFR-1, are provided with their appropriate ligand during acute renal injury, and therefore may contribute to apoptosis of renal tubular cells in acute renal failure.
Interestingly, increased production of TNF by renal tubular cells during ischemia appears to be mediated by activation of p38, a member of the mitogen-activated protein kinase (MAPK) family of kinases [48]. Almost all current evidence to support a role for Fas and TNF in acute renal failure is derived from studies in vitro in cultured renal tubular cells. More studies using experimental models of acute renal failure are needed to firmly establish the importance of FasL and TNFR-1 in acute renal failure in vivo during sepsis.
Coagulation
The activation of coagulation and deposition of fibrin in the tissues is a well- defined component of sepsis-related MOF. 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 coagula- tion 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 organ dys- function, 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 and inflammatory cell infiltration, and fewer fibrin clots than in untreated animals [51]. Activated protein C improves outcomes in sepsis, and it is currently unclear whether it also attenuates sepsis-associated acute renal failure [52].
Renal Recovery following Acute Renal Failure
Following sub-lethal cell injury, renal tubular cells undergo repair, regeneration, and proliferation (Fig. 1). The first phase of this regeneration process consists of the death and exfoliation of irreversibly injured cells and is characterized by stress response gene expression and infiltration by mononuclear cells [53]. Subsequently many quiescent renal tubular cells enter the cell cycle and undergo either repair or death. This decision point is carefully regulated and cyclin-dependent kinase inhibitors, especially p21, play an important role [54]. Growth factors may play a role in determining the fate of the epithelial cells and may contribute to the generation of signals that result in neutrophil and monocyte infiltration. In the second phase, poorly differentiated epithelial cells appear, which are believed to represent a population of stem cells residing in the kidney [55]. This stage is a dedifferentiation stage. In the third phase, a marked increase in proliferation of the surviving proximal tubule cells is evident and here growth factors may play an important role in this response [56]. In this last phase, the regenerative tubular cells regain their differentiated character and produce a normal proximal tubule epithelium.
A number of growth factors that have anti-apoptotic as well as pro-proliferation effects have been evaluated in acute renal failure. Unfortunately, early clinical tri- als have not yielded consistent results. However, two agents, bone morphogenic protein-7 (BMP-7) and erythropoietin, have promising, albeit largely hypothetical, effects on renal tubular cells [57]. Recent stem cell research shows that hematopoi- etic stem cells and other tissue specific stem cells are capable of crossing tissue and even germ-line barriers and can give rise to a remarkable range of cell types [58].
This plasticity of stem cells is thought to be useful in therapeutic strategies designed to enhance tissue regeneration after severe organ injury. Traditionally, stem cells were believed to be organ specific. However, experiments with whole-bone marrow transplantation demonstrated that bone marrow-derived stem cells could populate the renal tubular epithelium [59]. More recently, injection of mesenchymal stem cells of bone marrow origin has been shown to protect from severe tubular injury and subsequent renal failure in animal models of acute renal failure [60].
Conclusion
Development of acute renal failure during sepsis syndrome is common and por- tends a poor outcome. The interplay between systemic host responses, local insults
in the kidney, vascular bed, and immune system, all play a role in the development of sepsis-induced acute renal failure. Despite advances in critical care, mortality rates have remained high for sepsis-associated acute renal failure. This may be, in part, a function of our poor understanding of the mechanisms of sepsis-induced acute renal failure, leading to misguided management strategies for acute renal fail- ure. Improved understanding of various emerging mechanisms of sepsis-induced acute renal failure such as epithelial barrier dysfunction, apoptosis, and cytokine- mediated injury, should open newer avenues of therapeutic targets in this field.
As has often been the case in the study of sepsis, simple universal mechanisms such as tissue perfusion, have failed to explain the diverse and complex clinical response, and therapeutic strategies aimed at single mechanisms have not been successful. The pathophysiologic mechanisms now understood to be operative in sepsis-induced acute renal failure overlap and interact at many levels. Therefore, therapeutic strategies to prevent acute renal failure or to facilitate recovery will likely need to be multifaceted.
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