Neutrophils and renal failure

PHYSIOLOGY AND CELL BIOLOGY UPDATE

Neutrophils and Renal Failure Michael Heinzelmann, MD, PhD, Mark A. Mercer-Jones, MD, and John C. Passmore, PhD ● In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils’ ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This review summarizes the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. Nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase is a membrane-associated enzyme that generates a family of reactive oxygen intermediates (ROI). There is increasing evidence that ROIs are implicated in glomerular pathophysiology: ROIs contribute to the development of proteinuria, alter glomerular filtration rate, and induce morphological changes in glomerular cells. Specific neutrophil granules contain microbicidal peptides, proteins, and proteolytic enzymes, which mediate the dissolution of extracellular matrix, harm cell structures or cell function, and induce acute and potentially irreparable damage. Although both ROI and neutrophil-derived proteases alone have the potential for tissue destruction, it is their synergism that circumvents the intrinsic barriers designed to protect the host. Even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of neutrophil-derived myeloperoxidase (MPO) and initiate the deactivation of antiproteases and activation of latent proteases, which lead to tissue damage if not properly controlled. In addition, neutrophil-derived phospholipase products such as leukotrienes and platelet-activating factor contribute to vascular changes in acute inflammation and amplify tissue damage. Increasing evidence suggests that mesangial cells and neutrophils release chemotactic substances (eg, interleukin 8), which further promote neutrophil migration to the kidney, activate neutrophils, and increase glomerular injury. Also, the expression of adhesion molecules (eg, intercellular adhesion molecule 1 on kidney-specific cells and beta-2integrins on leukocytes) has been correlated with the degree of injury in various forms of glomerulonephritis or after ischemia and reperfusion. Together, these results suggest that neutrophils and adhesion molecules play an important role in mediating tissue injury with subsequent renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase susceptibility to infection and sepsis. 娀 1999 by the National Kidney Foundation, Inc. INDEX WORDS: Neutrophils; kidney disease; inflammation; tissue injury; reactive oxygen intermediates; adhesion molecules; integrins, phospholipase products.

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LOMERULAR DISEASES are the major cause of chronic renal failure, whereas acute renal failure occurs as a consequence of trauma, sepsis, hemorrhage with resuscitation, or ischemia-reperfusion injury.1-6 Knowledge of the mechanisms that are associated with glomerular injury is still incomplete despite intensive research. Controversies regarding the pathogenesis of acute renal failure include (1) whether acute renal failure is an acute tubular necrosis or a vasomotor phenomenon; (2) whether there is a From the Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY, and The Price Institute of Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, KY. Received March 25, 1998; accepted in revised form February 5, 1999. Address reprint requests to Michael Heinzelmann, MD, PhD, c/o M. Abby, Editorial Offıce, Department of Surgery, University of Louisville, Louisville, KY 40292. E-mail: [email protected]

娀 1999 by the National Kidney Foundation, Inc. 0272-6386/99/3402-0030$3.00/0 384

dominant biochemical mechanism of injury, (3) whether experimental models accurately reflect clinical acute renal failure, and (4) under what conditions ‘‘good molecules become bad.’’7 However, there is increasing evidence that leukocytes, particularly neutrophils, mediate tissue injury and play key roles in the development of renal failure.8-14 This experimental evidence derives from morphological studies that show an accumulation of neutrophils in ischemic acute renal failure, neutrophil depletion studies that show a reduction of tissue injury in the absence of neutrophils, and studies that show a benefit of anti-adhesion treatment on the course of experimental renal failure. In many diseases and acute inflammatory disorders, important components of pathological processes are linked to the neutrophils’ ability to release a complex assortment of agents that can destroy normal cells and dissolve connective tissue. This hypothesis is supported by evidence that neutropenic animal models show attenuated vascular injury in many diseases other than renal

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failure.8 Conversely, renal injury can clearly occur by neutrophil-independent pathways, as seen in neutropenic patients who develop acute renal failure, indicating that neutrophils are a factor, but not the only factor, that contributes to acute renal failure. This review discusses the mechanisms of tissue destruction by neutrophils and the role of kidney-specific factors that promote this effect. We outline neutrophil activation with special emphasis on integrins, and we review the effects of chronic renal failure and hemodialysis on neutrophil function. EVIDENCE OF NEUTROPHIL-DERIVED RENAL INJURY

The role of neutrophils in acute renal failure has been addressed in many studies and remains controversial.13,14 When Paller15 studied renal ischemia in rats that were depleted of neutrophils by antineutrophil serum, no difference in renal function was found when compared with control rats. Similarly, Thornton et al16 used antiserum to deplete neutrophils and produced renal ischemia for 50 minutes. Again, no difference in renal impairment between neutrophil-depleted and control animals were reported. In the same study, Thorton et al16 used a monoclonal antibody to CD18, a leukocyte adhesion molecule that promotes sticking to endothelial cells, and showed no protection against renal injury when compared with control experiments. In contrast to those negative results,15,16 a large body of experimental evidence indicates an important role of neutrophils in renal injury. Linas et al17-21 studied the effect of neutrophils in acute renal injury. In one of their experimental models, they used in vivo ischemia followed by kidney isolation and ex vivo perfusion. These authors showed that neutrophils contribute to ischemia-reperfusion injury as documented by morphological lesions and reduction of glomerular filtration rate.17 Furthermore, they showed that the number of neutrophils retained in the kidney was dependent on the duration of renal ischemia and the activity state of the neutrophil.18 When Willinger et al22 studied the tissue distribution of neutrophils from ischemic rats, they found that 45 minutes of ischemia followed by 120 minutes of reperfusion increased the neutrophil count by a factor of 8 in the cortex and

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by a factor of 12 in the outer medulla. In an earlier study, Hellberg and Kallskog23 described a 9-fold increase in neutrophils in the cortex and glomeruli. Importantly, these authors showed a protection of renal injury when rats were depleted of neutrophils before ischemia. These findings were confirmed in other studies to substantiate the destructive role of neutrophils in renal ischemia and reperfusion injury.24,25 MECHANISMS OF TISSUE DESTRUCTION BY NEUTROPHILS

The extracellular release of neutrophil cytotoxic products was initially attributed to neutrophil death within the inflammatory lesion. However, it is now recognized that neutrophils can discharge these cytotoxic products into the extracellular space without dying.26 The cytotoxic substances can be divided into two groups, which for the most part also correspond with their localization within the cell.9 The plasma membrane of the triggered neutrophil is the site of nicotinamide adenine dinucleotide phosphate H (NADPH) oxidase, which generates a family of reactive oxidizing chemicals (reactive oxygen intermediates; ROI),9,27 whereas the specific granules contain microbicidal peptides, proteins, and enzymes.28 In addition, phospholipase products such as leukotrienes (LT) and platelet activating factor (PAF) contribute to vascular changes in acute inflammation and promote neutrophilmediated tissue damage (Fig 1). Oxidative Mechanisms The oxidative or respiratory burst in neutrophils is triggered by phagocytosis or when the pathway is activated by an appropriate stimulus in vivo. The oxidative burst results in a sequential production of ROIs. The NADPH oxidase system is a membrane-associated enzyme complex that participates in the generation of at least 3 oxygen metabolites: superoxide anion (O2●⫺), hydrogen peroxide (H2O2), and the hydroxyl radical OH●.27 The oxidase is inactive in unstimulated neutrophils, but triggered cells rapidly activate the enzyme system and begin to transfer electrons from cytosolic NADPH to oxygen dissolved in the extracellular fluid. Normally, one molecule of oxygen acts as an acceptor for a single, donated electron, resulting in the genera-

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Fig 1. Destructive potential of neutrophils. Neutrophil activation by various inflammatory triggers leads to generation of reactive oxygen intermediates (ROI) via the NADPH oxidase system, release of neutrophil granule contents such as myeloperoxidase (MPO) or proteases (elastase, collagenases, etc.), and production of phospholipase products such as leukotrienes (LT) and platelet-activating factor (PAF). Alone, ROI or proteases have the potential for tissue destruction. However, even small amounts of ROI can generate hypochlorus acid (HOCl) in the presence of MPO and initiate the deactivation of antiproteases and activation of latent proteases. If not properly controlled, these mechanisms can circumvent the intrinsic barriers designed to protect the host and lead to tissue injury. Phospholipase products contribute to vascular changes in acute inflammation and promote neutrophilmediated tissue damage.

tion of one molecule of the superoxide anion. 2O2 ⫹ NADPH —(NADPH oxidase)= 2O2●⫺ ⫹ NADP⫹ ⫹ H⫹ In turn, two molecules of O2●⫺ interact (spontaneously by dismutation reaction or by the catalytic action of superoxide dismutase, SOD) to generate one molecule of H2O2. ●⫺

2O2

●⫺

⫹

⫹ 2H —(SOD)= H2O2 ⫹ O2

Both O2 and H2O2 can react with a number of important biological substrates, but intact neutrophils appear to be somewhat limited in their ability to cause extracellular damage using either metabolite.9 The importance of the oxidative burst in the microbicidal activity of neutrophils is shown in the rare patient who has severe impairments in this pathway (ie, chronic granulomatous disease).26 These patients suffer from repeated infections and respond poorly to conventional therapy, which almost invariably leads to early death. Myeloperoxidase (MPO) is a neutrophilderived enzyme, previously known as verdoperoxidase, which reflects its green color and its ability to catalyze peroxidative reactions. MPO is the enzyme that generates the characteristic

greenish color of pus and other purulent fluids. Once discharged from the neutrophil, MPO alone exerts little, if any, effect. However, in combination with H2O2, purified MPO can oxidize the halides Cl⫺, Br⫺, or I⫺ and form destructive compounds. H2O2 ⫹ Cl⫺ ⫹ H⫹ —(MPO)= HOCl ⫹ H2O Quantitative analyses showed that 1 ⫻ 106 maximally triggered neutrophils produced approximately 2 ⫻ 107 mol of HOCl during a 2-hour period.9 This amount of HOCl was nearly entirely generated by neutrophil-derived H2O2. Such quantities of oxidant generated by neutrophils are impressive because HOCl is an extremely powerful oxidant that rapidly attacks a wide range of biologically relevant molecules. Indeed, at neutral pH, the 2 ⫻ 107 mol of HOCl generated by neutrophils is enough to destroy as many as 150 million Escherichia coli organisms in milliseconds.27 However, the importance of MPO oxyhyalides in neutrophil microbicidal activity is poorly understood. MPO deficiency has been reported to have little clinical importance, although some patients who are affected may suffer from severe Candida infections.27 Neutrophil-generated ROIs also influence other

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cellular functions. Superoxide and H2O2 may augment phagocytosis independently of the MPOhyalide system, and ROIs also promote the margination of neutrophils by triggering the expression of adhesion molecules on endothelial cells.26 In addition, ROIs have an essential role in signal transduction in leukocytes and other cells, such as in kidney and mesangial cells.29 For a detailed review, see the summary by Lander,29 in which the investigator discusses how ROI can achieve specificity and in which he explores some pathophysiological implications of ROIs. Shah30 provided further evidence that ROIs are implicated in glomerular pathophysiology. The effects of ROIs may contribute to the development of proteinuria, altered glomerular filtration rate, and morphological changes of glomerular cells. Various studies indicate that not only neutrophils but also mesangial cells and glomerular epithelial cells can be sources of ROI. Therefore, both resident glomerular cells and leukocytes can produce ROI with the potential for tissue injury.30 The connection between neutrophil ROI release and glomerular damage has been demonstrated by Linas et al.17 When neutrophils from a patient with granulomatous disease were reperfused to isolated ischemic kidneys, renal injury was not accentuated, contrasting the marked increase of injury in the kidneys that were perfused with normal control neutrophils. The only recognized defect in neutrophils from patients with granulomatous disease is the failure to produce superoxide, thus indicating a critical role of ROIs in neutrophil-mediated renal injury. In other experiments, scavenging H2O2 with catalase did not decrease injury in the absence of neutrophils but did decrease reperfusion injury in the presence of neutrophils, suggesting that ROIs derived from neutrophils and not from other resident cells substantially contribute to ischemic renal injury. The exact mechanisms by which ROI induce renal injury are unknown. We speculate that these effects are attributable to direct effects such as damage of lipids and proteins and, even more importantly, to indirect effects such as activation of proteinases, inactivation of antiproteinases, and modulation of signal transduction cascades.

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Nonoxidative Mechanisms Neutrophil granules contain many hydrolytic enzymes and antimicrobial polypeptides that can mediate vascular injury.8 For example, cationic proteins extracted from lysosomal granules increase vascular permeability in vivo. Proteases destroy vascular basement membranes in vitro and in vivo, and the neutrophil-derived protein heparanase rapidly degrades heparan sulfate in subendothelial matrix in vitro.31 The content of granules also includes lysozyme and collagenase, which destroy cell envelope components, acid hydrolases and antimicrobial defensins, which are contained in specific granules,32 and many proteolytic and saccharolytic enzymes, which digest microbial structural proteins and mucopolysaccharides. Interestingly, most of these proteins are positively charged, which enhances their binding to cell surfaces. Neutrophil granules contain more than 20 enzymes,28 but serine proteinase, elastase, and two metalloproteinases (collagenase and gelatinase) are probably the most potential mediators of tissue destruction in immunologic injury. Each of these proteinases can degrade key components of the extracellular matrix, which is composed of collagens, elastins, proteoglycans, and glycoproteins. The matrix not only serves as an extracellular framework that maintains tissue architecture but also serves as an interactive interface that regulates the shape, migration, growth, and differentiation of a variety of cells.33 Thus, neutrophilmediated dissolution of the extracellular matrix can harm cell structures or cell function and induce acute and potentially irreparable damage. In many respects, it is amazing that neutrophil granules contain large quantities of enzymes that not only can easily degrade nearly all components of the extracellular matrix but also can cleave a variety of key plasma proteins (eg, immunoglobulins, complement proteins, clotting factors), and even attack intact cells.34 Indeed, because elastase is able to mediate extracellular damage, its physiological action was thought to be restricted to the phagocytic vacuole, where elastase participates in the destruction and digestion of phagocytosed microorganisms. This concept was supported by the fact that plasma and interstitial fluids are known to contain a series of powerful antiproteinases that can effectively regu-

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late extracellular neutrophil elastase and prevent the enzyme from damaging extracellular substrates.35 Among these inhibitors, the host’s primary defense against uncontrolled elastase-mediated damage, is alpha1-proteinase inhibitor, a 52-kd glycoprotein (formerly termed alpha1-antitrypsin) that irreversibly inhibits neutrophil elastase by forming an enzyme-inhibitor complex. Indeed, the calculated half-life of active elastase is only about 0.6 msec, and all activity is thought to be inhibited by 3 msec.35 Given the effectiveness of these inhibitors, it seems reasonable to assume that neutrophil elastase does not mediate extracellular tissue damage under physiological conditions. However, if the antiproteinase shield can be avoided, neutrophils are able to use the discharged elastase to attack and destroy host tissues.9 While studying the degradation of type IV collagen in the glomerular basement membrane, Donovan et al36 found a predominant role for neutrophil-derived elastase. These studies were performed in an in vitro model and showed that specific elastase inhibitors (alpha1-proteinase inhibitor and the smaller highly specific synthetic compound L658,758) reduced glomerular basement membrane degradation. Importantly, the scavenging of neutrophil-derived ROI generation did not alter elastase release but reduced glomerular membrane damage by inhibiting the effect of alpha1-proteinase inhibitor. Consistent with this paradigm, other studies showed that both ROI scavengers and elastase inhibitors were necessary to prevent neutrophil-mediated renal injury.21 Of the 10 antimicrobial proteins identified so far, lysozyme and bactericidal-permeability increasing protein seem to be unique in their primary structure. The remaining 8 can be divided into two families: defensins and serine protease homologues.37 Although defensins are primarily synthesized by neutrophils, they are also produced by other cells such as Paneth cells in the small intestine38 or in bovine tracheal mucosa.39 Many of these granule constituents were originally studied because of their antibiotic activity, but it became increasingly evident that these substances have other important roles during inflammation.40 It is not clear whether these antimicrobial proteins directly damage tissue and

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contribute to renal failure. However, certain antimicrobial proteins have a variety of functions, which are not related to the antimicrobial activity but clearly modulate the inflammatory response. For example, bactericidal permeability-increasing protein, which is located in the primary granules of neutrophils, is a very potent antibacterial agent directed specifically at a broad range of gram-negative bacterial species. Its known functions include potent growth-inhibitory activity against a wide range of gram-negative bacteria and the ability to inhibit the biological activity of endotoxin, both in whole blood ex vivo and in animal models of experimental sepsis.28,41 Another example is cationic antimicrobial protein 37 (CAP37, also known as azurocidin or heparin-binding protein). CAP37 is released from activated neutrophils and has many effects on monocytes, including chemotaxis, increased longevity,42 and the enhancement of lipopolysaccharide (LPS)-induced proinflammatory mediators such as tumor necrosis factor-␣ (TNF-␣) or prostaglandin E2 (PGE2) production.43,44 Proinflammatory cytokines such as TNF-␣ and interleukin (IL)-1 have major effects on renal function in sepsis, both systematically and locally.45 In addition to monocytes and mesangial cells, neutrophils also release cytokines, such as TNF-␣, IL-1, IL-6, and IL-8.46,47 Hence, neutrophils also modulate T- and B-cell activity and neutrophil chemotaxis to indicate an important role of neutrophils in the afferent limb of inflammation.46 Synergism of Oxidative and Nonoxidative Mechanisms When neutrophils are triggered by proinflammatory stimuli, the oxidase begins to generate and release oxygen metabolites. Almost simultaneously, granules fuse with the plasma membrane and discharge their contents both into the extracellular compartment and into the phagocytic vacuole. Reactive oxygen intermediates have consistently been considered to be the most destructive substances released from the cell, but it is evident that proteolytic enzymes also have an important role. In fact, it is not likely that oxygen metabolites or proteolytic enzymes alone are solely responsible for the neutrophil-derived tissue damage in vivo. Rather, it seems evident that neutrophils are designed to use both the NADPH oxidase system and the granule constitu-

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ents in a cooperative and additive manner. It is the combination of these components that ultimately leads to tissue damage.9 Powerful oxidants are, by nature, short-lived and nonspecific. The effect of proteinases is controlled by an inborn latency and by highly effective antiproteinases. Acting alone, either set of weapons would exert only very localized effects. However, acting in combination, small amounts of hypochlorous acid and proteinases are capable of circumventing the intrinsic barriers that were designated to protect the host from injury. The oxidative inactivation of a series of key proteinase inhibitors with simultaneous activation of latent proteinases allows the neutrophils to cleverly create an environment in which elastase, collagenase, and gelatinase are able to maximize their destructive effects and act with greater efficacy than even enormous doses of ROIs could alone. It seems that ROIs, proteinases, and antiproteinases paradoxically interact to allow neutrophils to maximize their ability to damage host tissues. Oxidants and proteinases are released into an extracellular environment in which there are little or no enzymes that diminish concentration of ROIs. Relatively small concentrations of ROIs are capable of turning proteinases on and antiproteinases off. This highly destructive design is needed in normal host defense to cross connective tissue barriers, to dissolve infected tissue, or to participate in abscess formation.48 In a physiological inflammatory response, neutrophils do not continuously degrade host tissue, because the neutrophil influx and activation is carefully regulated and stops when the initiating trigger is eliminated. If the oxidizing environment has been resolved, the inactivation of antiproteinases is terminated, and functionally active antiproteinases either diffuse from the plasma to the inflamed site or are produced locally.49 However, if the initiating trigger persists, or if inflammatory stimuli are not properly downregulated, the neutrophil-derived destructive substances can penetrate all of the host’s defenses, with devastating consequences. Phospholipase Products Products of membrane phospholipases may contribute significantly to vascular changes in

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acute inflammation,50 and neutrophils can be an important source of these mediators.8 The metabolism of arachidonic acid produces an array of metabolites, known as eicosanoids, with great diversity of biological activity. At least three families of enzymes are involved in the metabolism of arachidonic acid: cyclooxygenase, lipooxygenase, and cytochrome p450. Both vasodilatory prostaglandins (PGE2 and prostacyclin) and vasoconstrictive eicosanoids (thromboxane A2) are synthesized by renal cortex and medulla.51 Eicosanoids are synthesized at or near the site of action and initiate their biological effects by binding to specific cell membrane receptors. Previous studies have demonstrated that, after inflammatory injury to the kidney, eicosanoid formation is increased in isolated glomeruli. Several studies have emphasized the role of intrarenal production of cyclooxygenase products such as thromboxane A2 and PGE2 in modulating renal hemodynamics and in mediating the reduction in glomerular filtration rate.51,52 In addition, there is increasing evidence that thromboxane A2 not only has vasoconstrictive properties but is also involved in the proliferatory response to glomerular immune injury and the resultant crescent formation.52 The lipo-oxygenase products LTC4 and LTD4 stimulate human endothelial cells to synthesize PGI2 and PAF and to bind neutrophils.53 LTB4 is a potent chemoattractant that activates neutrophils and suggests that LTB4 contributes to neutrophil-induced tissue injury and renal failure. A strong correlation was found between LTB4 and neutrophil infiltration in nephrotoxic seruminduced nephritis, a model of inflammatory glomerular injury in the rat.54 Leukotrienes, together with many other mediators such as TNF-␣, IL-1, PAF, or thromboxane A2, are likely to have a role in the development of endotoxic shock.55 During sepsis, leukotriene generation is increased by two mechanisms: first, endotoxin stimulates production of leukotrienes from neutrophils and other inflammatory cells,56 and second, endotoxemia markedly retards biliary elimination of the end-products of leukotriene metabolism in vivo, thereby increasing the plasma levels of these end-products.57 Interestingly, not all leukotrienes have proinflammatory properties, but some 15lipo-oxygenase products also have multifaceted counterinflammatory actions in the renal glomeru-

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lus, as demonstrated for 15-S-HETE and LXA4.58 In general, HETEs have an inhibitory action on arachidonic acid metabolism via the cyclooxygenase pathway, and the concentrations required to achieve such inhibition in vivo most likely reflect local accumulation, either intracellularly or at the membrane, rather than circulating levels.50 Badr and Lakkis58 also emphasized the role of neutrophils as ‘‘early’’ cells after immunecomplex glomerulonephritis (GN), with mediators of injury including ROI, 5-lipooxygenase, and cyclooxygenase arachidonate metabolites. Platelet-activating factor (PAF) is a pleiotropic mediator of inflammation that also has direct effects on microvascular permeability and vasomotor tone in vivo. A variety of cells, including neutrophils, macrophages, endothelial cells, and glomerular cells, can produce PAF. Infusion of PAF in vivo causes a reduction of glomerular filtration rate (GFR) and renal blood pressure and a reduction of urine output and Na⫹ excretion.59 Using the model of reperfusion of cold ischemic kidney with neutrophils, Riera et al25 showed that treatment with a PAF receptor antagonist attenuated renal blood flow, GFR, and Na⫹ reabsorption in a dose-dependent manner, suggesting that renal injury is mediated by PAF. When Wang and Dunn60 studied the role of PAF in experimental endotoxemia in rats, they found that endotoxin (150 µg/kg) reduced GFR, renal plasma flow, and filtration fraction without a change in mean arterial pressure. Blockade of PAF receptors with L-652,731 prevented the endotoxin-induced changes, suggesting that PAF may play an important role in mediating the endotoxin-induced acute renal insufficiency. Von Asmuth and Buurman61 have shown that endothelium actively participates in TNFinduced neutrophil respiratory burst activity by expressing PAF in response to initial neutrophil H2O2 release. Koltai et al62 summarized the involvement of PAF in acute renal failure by demonstrating a protective effect of PAF receptor antagonist in the later phase of shock. This effect was associated with significant improvement of hemodynamic changes, kidney function, and a profound decrease in LPS-induced thromboxane B2 release. Together, these data indicate that PAF and other phospholipase products have the potential to induce tissue injury and renal failure. Although neutrophils produce phospholipase

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products and PAF, it is likely that other cells such as mesangial cells substantially contribute to the concentration required to induce renal failure. However, experimental evidence is lacking to substantiate this hypothesis. ROLE OF CHEMOKINES AND ADHESION MOLECULES IN NEUTROPHIL-MEDIATED VASCULAR INJURY

It is obvious that neutrophil-mediated renal failure cannot occur when neutrophils are not attracted to the site of inflammation and when neutrophils do not accumulate in the kidney. Therefore, adhesion molecules and chemokines play a pivotal role in recruiting neutrophils and in mediating tissue injury.63-65 The migration of neutrophils and other leukocytes from the blood to the site of inflammation is a multistep process that is sequentially mediated by a variety of molecules on leukocytes and endothelial cells. Selectins (P- and E-selectins on the endothelium and L-selectins on leukocytes) are responsible for the initial rolling, whereas ␤2-integrins (eg, CD11a/CD18 and CD11b/CD18 on leukocytes) and members of the immunoglobulin superfamily (eg, intracellular adhesion molecule-1 [ICAM1] and ICAM-2 on endothelium) are responsible for sticking and firm adhesion. Chemokines are involved in (1) attracting leukocytes to the site of inflammation, (2) activating leukocytes after the initial rolling, and (3) facilitating transendothelial migration of leukocytes.65,66 Chemokines Chemokines are a family of small (⬍10 kd), basic, heparin-binding polypeptides with four conserved cysteine residues that form two disulfide bonds. Chemokines can be divided into two subfamilies based on the position of the first two cysteine amino acid residues in the molecule.66-68 The C-X-C subfamily, in which the two cysteine residues are separated by an intervening amino acid, is best represented by IL-8, a strong neutrophil chemoattractant peptide. In the C-C subfamily, the cysteine residues are adjacent to each other. This second subfamily is best characterized by the effects of monocyte chemoattractant protein-1 (MCP-1) and RANTES (regulated on activation, normal T expressed and secreted). Infiltration of leukocytes into the glomerulum is often associated with renal disease. In addition, a

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close time relationship between chemokine expression and leukocyte infiltration indicates not only an association but a functional correlation.69 It is becoming increasingly evident that mesangial cells, together with endothelial epithelial cells, do not play a simple bystander role in inflammatory disorders but actively participate in the initiation and maintenance of glomerular inflammation by synthesizing a variety of cytokines, chemokines, eicosanoids, and growth factors.70 Mesangial cells play a key role in the kidney. Not only do they control the rate of glomerular filtration, but they also maintain the integrity of the glomerulus via matrix synthesis and provide support for the capillary loops. The following properties of chemokines are especially important for the regulation of leukocyte recruitment. Binding of cationic chemokines to structures on the surface of the endothelium such as glycosaminoglycans results in the generation of a fixed chemotactic gradient and prevents dilution by flowing blood. Furthermore, the activating effect of the bound chemokine is confined to the local area of the inflammatory process. This form of chemotaxis is termed haptotaxis. Chemokine mRNA expression and synthesis of IL-8, MCP-1, and RANTES has been observed in cultured human glomerular mesangial, epithelial, and tubular epithelial cells on stimulation with IL-1, TNF-␣, interferon-␥, or LPS.70 The importance of chemokines in the generation of glomerular injury in vivo has been demonstrated by Wu et al.71 In a rat model, the authors showed that the kinetics of neutrophil-specific chemokine mRNA expression in response to IL-1␤ and TNF-␣ paralleled with those of neutrophil migration during nephritis in vivo. Wu et al72 also studied the role of chemokines in antiglomerular basement nephritis. These authors showed that CXC chemokine expression was monophasic and paralleled neutrophil influx, whereas CC chemokine expression was biphasic, with peaks coinciding with the influx of neutrophil and macrophages. Importantly, neutralizing antibodies to MIP-1 ␣ (a CC chemokine) attenuated the acute phase proteinuria, but not the accompanying neutrophil influx, whereas neutralizing antibodies to cytokine-induced neutrophil chemoattractant (a CXC chemokine) inhibited both neutrophil influx and proteinuria. Together,

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these data indicate that an influx of myeloid cells is necessary for local chemokine expression. Using a model of immune complex-induced glomerulonephritis in rabbits, Wada et al73 showed that anti–IL-8 antibody treatment decreased the number of neutrophils in glomeruli by 40% and completely normalized the urinary levels of protein and albumin, indicating that neutrophils attracted by IL-8 contribute to renal dysfunction. The events that lead to leukocyte motility are complex processes that depend on the coordination of many cellular functions. The link between the extracellular and intracellular environments, such as transmembrane signaling events that lead to activation in the actin cytoskeleton, have been summarized by Downey74 and go beyond the focus of this review. Adhesion Molecules Various studies have shown an involvement of adhesion molecules in renal diseases.75-80 Lhotta et al75 found increased glomerular staining of ICAM-1 in about half of all the biopsy specimens from patients with glomerular nephritis (GN). In the normal kidney, ICAM-1 was expressed on endothelial cells, on cells of glomerular and peritubular capillaries, on Bowman’s capsule on some interstitial cells, and weakly in the mesangium. De novo expression of ICAM-1 was noted on tubular epithelial cells in rapidly progressive GN and membranoproliferative GN. In 63% of positive tubuli, leukocytes expressing CD18 were present in the tubular lumen. In a similar study, Chow et al76 correlated the ICAM-1 positivity in damaged and undamaged tubules in three groups of renal diseases: nonimmune renal disease, low-grade GN, and high-grade GN. They showed that ICAM-1 positivity in undamaged tubuli was observed in GN and correlated strongly with disease activity, and that ICAM-1 positivity on damaged tubules correlated with evidence of chronic tubular damage, regardless of the underlying disease. These studies indicate that renal ICAM-1 expression may be used as a marker for certain kidney diseases. Mulligan et al78 studied the requirements of adhesion molecules in a rat model of GN induced by antibodies against glomerular basement membrane. Proteinuria at 24 hours and neutrophil accumulation in renal glomeruli at 6 hours were used as endpoints. The results indicate a differen-

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tial role of cytokines and adhesion molecules. Maximal neutrophil accumulation in glomeruli as well as full development of proteinuria was correlated with TNF-␣, a very late activating antigen-4 (VLA-4, CD49d/CD29), ICAM-1, and CD11b, but not IL-1, CD11a, or E-selectin. In a study of crescentic GN in rats, Nishikawa et al77 showed that the administration of monoclonal antibodies against ICAM-1 and CD11a/CD18 markedly decreased the severity of the renal disease. They concluded that this preventive or therapeutic effect probably resulted from interference with the interaction between leukocytes and activated glomerular endothelium. Alexopoulos et al81 showed that patients with proteinuric immunoglobulin A (IgA) nephropathy expressed more CD11a and CD18 on interstitial leukocytes when compared with patients with nonproteinuric IgA nephropathy. There was no difference in the total leukocyte count, and there was no difference of CD11a/CD18 expression in leukocytes analyzed in the glomeruli. These results suggest that the amount of CD11a/ CD18 expression on interstitial leukocytes correlates with kidney injury in IgA nephropathy. The authors, by using monoclonal antibodies against CD3 (T cells) and CD68 (monocytes/macrophages), also analyzed leukocyte subsets and identified a large number of T cells and monocytes/macrophages in both groups.81 However, the percentage of glomerular leukocytes that were CD3- or CD68-negative, presumably granulocytes, was different. The authors did not analyze these results to estimate the percentage of neutrophils. However, it can be calculated from their data that the group with nonproteinuric IgA nephropathy had 10% CD3- and CD68-negative leukocytes (presumably neutrophils) per glomerulus when compared with 17% in the proteinuric IgA nephropathy group. These results indicate that neutrophils could be involved in the generation of proteinuric IgA nephropathy. In a similar study, Naiker et al82 analyzed leukocyte subsets using histopathologic sections of patients with membranoproliferative GN. The authors found an increase of total interstitial leukocyte count, T cells, and B cells, but no increase in the number of interstitial monocytes when compared with the control group (patients with nonproliferative forms of GN). They also reported a correlation between the total leuko-

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cyte count in the infiltrates with impaired renal function, as measured by serum creatinine and creatinine clearance. In the group with membranoproliferative GN, total interstitial leukocyte count (measured in cells/mm2) was 1,306 ⫾ 1,254, and the percentage of cells that were not T cells, B cells, or monocytes (and therefore presumably neutrophils) was 29.4%. Patients with nonproliferative GN had 10-fold reduced total leukocyte count (138 ⫾ 91). However, the sum of T cells (42 ⫾ 60), B cells (57 ⫾ 50), and monocytes (54 ⫾ 59) exceeded the total leukocyte count. This data presentation did not allow us to estimate the number of neutrophils in the control group. Thus, this study indicates that a leukocyte subset other than monocytes is involved in the pathophysiology of membranoproliferative GN.82 Studies of ischemia-reperfusion injury in rats showed that the CD11/CD18 leukocyte adhesion pathway plays a role in mediating acute renal failure,80 that neutrophils accentuate ischemia reperfusion injury,20 and that neutrophils accumulate particularly within peritubular capillaries in the cortex and within the inner stripe of the outer medulla.22 The protective effects of treatment with anti-CD18 antibodies have been observed in a wide variety of other neutrophil-mediated inflammatory injuries.83,84 Also, many studies have reported benefits of anti–ICAM-1 therapies in ischemia-reperfusion or acute inflammation.6,83 Using a model of nephrotoxic nephritis, Wu et al85 showed that administration of the anti-CD11b monoclonal antibody OX42 16 hours before disease induction led to a substantial decrease in proteinuria (80%) and decreased the number of neutrophils found in the glomerulus. This study underlines the important role of neutrophils in nephrotoxic nephritis. Another approach to inhibit leukocyte-endothelial adhesion is to block endothelial receptors such as ICAM-1 or ICAM-2.65 Studies using monoclonal antibodies, ICAM-1–deficient mice, and antisense nucleotide for ICAM-1 were used to show an important link between adhesion molecules and neutrophils in the pathogenesis of renal failure. Using serum creatinine, renal histology, and animal survival as surrogate markers, Kelly et al86 showed that renal leukocyte infiltration was markedly less in ICAM-1–deficient than in control mice. The authors further evalu-

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ated whether prevention of neutrophil infiltration could be responsible for the protection observed in the mutant mice. They treated normal mice with antineutrophil serum to reduce absolute neutrophil counts. The neutrophil-depleted animals were protected against ischemic renal failure.86 Furthermore, anti–ICAM-1 antibody protected normal mice against renal ischemic injury, even when given 2 hours after the ischemic period,87 but did not provide additional protection to neutrophil-depleted animals.86 Haller et al88 showed that antisense oligonucleotides for ICAM-1 protected the kidney against ischemic injury. Serum creatinine and urea concentrations 12 and 24 hours after ischemia were increased in control treated rats when compared with antisense oligonucleotide-treated or sham-operated rats. Antisense oligonucleotides also ameliorated the ischemia-induced infiltration of granulocytes and macrophages. Using a model of isolated perfused kidney and anti–ICAM-1 antibodies, Linas et al18 found that neutrophil sequestration after ischemia was ICAM-1 dependent. In further studies, catalase was used to scavenge ROIs and indicated that endothelial ICAM-1 expression was dependent on ROIs. Importantly, reperfusion of ischemic kidneys with catalase prevented ICAM-1–dependent neutrophil sequestration as well as neutrophil activation and tissue injury. In control experiments, perfusion of nonischemic kidneys with hydrogen peroxide caused sequestration and activation of primed neutrophils as well as tissue injury. Together, these studies indicate that ischemic kidneys cause neutrophil sequestration and tissue injury by mechanisms that include ROIdependent upregulation of endothelial ICAM-1. ROLE OF INTEGRINS IN NEUTROPHIL ACTIVATION

The recognition of integrins as a widely expressed family of cell surface adhesion receptors dates back 10 years.89 Integrins appear to be the major receptors by which cells attach to the extracellular matrix, and some integrins also mediate important cell-cell interactions. All integrins are heterodimers of ␣ and ␤ subunits that can pair to form more than 20 receptors.89 They generally contain a large extracellular domain formed by the ␣-and ␤-subunits, a transmem-

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brane segment from each subunit, and two short cytoplasmic C-terminal tails. The ␤-subunit interacts with the actin cytoskeleton through several intermediary molecules, including ␣-actin, vinculin, talin, paxillin, and tensin.90 Hence, it is not surprising that many cell functions such as mitosis, migration, and differentiation are modulated by integrins. Two key features of integrin function (Fig 2) make these receptors of particular interest: regulation from within the cell (insideout signaling) and modulation of cellular behavior by extracellular matrix (outside-in signaling).89

Fig 2. Signaling of integrins. (A) Inside-out signaling. Cell-specific cytoplasmic signals target the intracellular domain of the integrin. The unidentified factor(s) responsible for these signals, shown as integrin activator complex (IAC), interact with the cytoplasmic domains and induce conformational changes in the integrin ␣- and ␤-subunits. This conformational change subsequently alters the affinity for the ligand. (B) Outside-in signaling. Binding of ligand to the extracelluar domain of the integrin replaces a divalent cation (ⴙⴙ) and induces a change in conformation. This conformational change promotes binding of the cytoplasmic domain to the cytoskeleton. Modified with permission, from the Annual Review of Cell and Developmental Biology Volume 11, 娀 1995, by Annual Reviews Inc.90

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The potential pathophysiological importance of integrins expressed on renal tubule cells for acute renal failure include acute changes of junctional permeability, cytoskeletal alteration, and post-acute effects involved in reparative processes. The precise role of integrins in kidney dysfunction, especially the tubular cell function, remains unknown, and therefore their role in acute renal failure remains speculative.91 However, it is likely that many integrins will prove to be important in the generation and maintenance of acute renal failure. Inside-Out Signaling: Affınity Modulation of Leukocyte Integrins ␤2 integrins that are constitutively expressed on leukocytes are normally inactive and bind only with very low avidity to their ligands. They can be triggered remotely via other membrane receptors, such as chemokine receptors, to cause leukocyte activation. This ‘‘inside-out’’ signaling increases the avidity of integrins and leads to firm adhesion to endothelial cells or leukocytes bearing integrin counter-receptors such as ICAM-1. Signal transduction for neutrophil activation is not a ligand-receptor interaction for a single substance but includes a variety of ligands, receptors, and second messengers.92 Chemotactic agonists such as IL-8, LTB4, and PAF have already been mentioned. Other chemotactic substances include complement C5a, formed on complement activation, and N-formylmethionyl oligopeptides such as fMet-Leu-Phe, which are derived from mitochondria of damaged tissues or from bacteria. The common feature of this heterogenic ligand population is the binding to a family of receptors that have 7-transmembrane-segment receptors and share sequence similarities.67 Ligand-receptor interaction, which is the first event in signal transduction, has to persist to sustain the response. Many pathways of signal transduction have been described, including guanosine 5’-triphosphate-binding-proteins (G-proteins), phospholipases (eg, phospholipase A2, C, D), Ca⫹⫹-dependent and Ca⫹⫹independent mechanisms, and protein kinases (eg, serine/threonine or tyrosine phosphorylation).92 As a consequence, these intracellular signals can increase ligand-binding affinity of other receptors such as integrins.90 The working model of affinity modulation of integrins is sum-

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marized in Fig 2A. The cytoplasmic domain of the integrins is targeted by specific, energydependent cytoplasmic signals. These signals are directed by so far unidentified factors that lead to changes in spatial relationships or conformations of the ␣ and ␤ subunit. Such changes transverse the membrane-proximal domain of the integrin and, ultimately, the conformation of the extracellular domain and its affinity for its ligand. Outside-in Signaling: Signal Transduction by Integrins Integrins regulate cell functions and behavior in nearly every cell type. Replication of normal adherent cells such as fibroblasts and endothelial cells requires anchorage to a solid substrate. Integrins form this physical link between the cytoskeleton and the extracellular matrix.93 The activation of leukocytes is also regulated by adhesion to the extracellular matrix. Secretion of cytokines such as IL-1 by monocytes is stimulated by integrin-mediated adhesion or by crosslinking of integrins with antibodies.94,95 The ability of leukocytes to respond to cytokines or opsonized particles is strongly enhanced by adhesion. The binding of immobilized immunoglobulin G particles via Fc receptors is independent of integrins, but subsequent phagocytosis of small immunoglobulin G–coated particles and the activation of respiratory burst are enhanced by extracellular matrix proteins. Interestingly, phagocytosis of particles opsonized by complement are mediated by the CR3 receptor, which is the CD11b/CD18 integrin. However, the signals activating neutrophil respiratory burst are not mediated by CD11b/CD18, but by CD11a/CD18 and CD11c/CD18,96 and especially by the Fc receptor.97 Blockade of CD11b/CD18 has little effect on binding but strongly inhibits subsequent phagocytosis of complement-coated beads.98,99 In addition, TNF-␣ synergizes with CD11b/CD18 to increase neutrophil cytotoxicity,100 which underlines the importance of synergistic effect of proinflammatory cytokines and neutrophil integrins. To date, several reports demonstrated ‘‘outsidein’’ signaling via ␤2 integrins in leukocytes: (1) stimulation with soluble ICAM-1 leads to signaling via CD11a/CD18 and phospholipase C-␥1 activation on T-cells,101 (2) immune-complex– stimulated production of neutrophil LTB4 is de-

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pendent on ␤2 integrins,102 (3) tyrosine phosphorylation of paxillin in neutrophils treated with TNF-␣ is ␤2 integrin dependent,103 and (4) soluble ICAM-1 provokes elastase release in neutrophils via CD18-dependent mechanisms.104 The working model of outside-in signal transduction of integrins is summarized in Fig 1B. Initially, the binding of a ligand to the extracellular domain replaces a divalent cation (⫹⫹). Subsequently, a change in conformation is induced and promotes binding of the cytoskeleton to the cytoplasmic domains of the integrin. However, the downstream events are not completely understood.90 These events include changes in intracellular pH and calcium, membrane potential, and lipid metabolism such as the activation of arachidonic acid by phospholipase A2, production of diacylglycerol with subsequent activation of protein kinase C, the activation of the guanosine triphosphate–binding protein Rho with subsequent activation of phosphatidylinositol phosphate 5 kinase, and activation of protein tyrosine kinases, including the focal adhesion kinase pp125FAK. Schwartz et al90 provide a detailed review of this subject. Integrin-mediated signal transduction appears to involve cooperative assembly of large multiprotein complexes of signaling and cytoskeletal proteins. Initial integrin occupancy and clustering (together with input from soluble factors) trigger the assembly of small complexes and generate the first cell signaling. These signals then induce assembly of larger complexes and further signaling events, which lead to cell spreading, focal contact formation, and transmission of regulatory signals.90 EFFECT OF CHRONIC RENAL FAILURE ON NEUTROPHIL FUNCTIONS

In the previous sections, we described the potential role of neutrophils in mediating vascular injury and acute renal failure. Conversely, renal failure, and particularly chronic renal failure with the need for hemodialysis, also can alter neutrophil function.105-108 Indeed, neutrophils from patients with chronic renal failure have been shown to (1) display reduced phagocytic ability,109 (2) decreased generation of ROI during oxidative burst,106,110 (3) impaired chemotactic ability,106,111,112 (4) significant elevation of resting levels of cytosolic calcium, and (5) reduc-

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tion in adenosine triphosphate content.113 In addition, within 30 minutes of hemodialysis, a profound leukopenia occurs, which is thought to be due to leukocyte sequestration in pulmonary capillaries as a result of complement C5a activation induced by the interaction with the dialyzer membrane.107 Various studies have shown that cellulose membranes have a considerable potential for complement activation and neutropenia.107 Incompatible membranes activate complement and delay resolution of acute renal failure. Using a rat model of acute renal failure, Schulman et al114 showed that exposure to cuprophane membrane significantly delayed recovery of renal failure, reduced GFR, and increased neutrophil infiltration when compared with control or polyacrylonitrile-exposed rats. In addition to complement activation, dialysis with cellulose membranes also increases the expression of the adhesion molecule CD11b/CD18 and activates neutrophils.115 Recent clinical studies show a correlation between membrane compatibility, that is, low complement activation, and outcome of renal failure.116-119 Dobos et al120 studied the effect of C5a pretreatment on receptor-mediated signal transduction and analyzed phosphatidyl inositol-4,5 biphosphate, cytosolic calcium levels, and superoxide production from patients with end-stage renal failure. They showed that the hydrolysis of phosphatidyl inositol-4,5 biphosphate in neutrophils from patients with end-stage renal failure did not differ in response to C5a when compared with healthy controls. They also found that resting calcium levels were significantly increased after priming with low C5a concentrations in both groups. The concomitant increase in superoxide production was significantly higher in neutrophils from healthy controls than in those from uremic patients, suggesting that priming induced superoxide production in neutrophils is reduced in patients with end-stage renal failure.120 Interestingly, neutrophils from continuous ambulatory peritoneal dialysis patients have a reduced surface expression of C5a receptors,107,121 possibly as a counterregulatory mechanism after chronically elevated C5a levels. Chervu et al108 showed in a rat model that animals are protected from impairment in phagocytosis by prior parathyroidectomy or by treatment with calcium channel blockers, suggesting that these changes were

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correlated with elevated parathyroid hormone, as seen in secondary hyperparathyroidism. CONCLUSIONS

Neutrophils have a large arsenal of powerful weapons and play a central role in host defense. However, the same weapons that protect the host also can lead to tissue damage and organ failure if not properly controlled. Some potentially harmful substances such as ROIs can contribute to additional tissue damage by activating proteases and deactivating antiproteases. It is the ultimate goal of the host defense, and any therapeutic intervention, to boost beneficial inflammatory responses without inducing adverse effects that may harm or even destroy organs. Morphological studies, neutrophil depletion studies, and antiadhesion studies provide ample evidence that neutrophils play an important role in renal failure. Conversely, chronic renal failure reduces neutrophil function and thereby can increase the susceptibility to infection and sepsis. REFERENCES 1. Faist E, Baue AE, Dittmer H, Heberer G: Multiple organ failure in polytrauma patients. J Trauma 23:775-787, 1983 2. Goris RJ, te Boekhorst TP, Nuytinck JK, Gimbrere JS: Multiple-organ failure: Generalized autodestructive inflammation? Arch Surg 120:1109-1115, 1985 3. Baue AE: Multiple organ failure, multiple organ dysfunction syndrome, and the systemic inflammatory response syndrome: Where do we stand? Shock 2:385-397, 1994 4. Barron RL: Pathophysiology of septic shock and implications for therapy. Clin Pharm 12:829-845, 1993 5. Natanson C, Hoffman WD, Suffredini AF, Eichacker PQ, Danner RL: Selected treatment strategies for septic shock based on proposed mechanisms of pathogenesis. Ann Intern Med 120:771-783, 1994 6. Granger DN, Korthuis RJ: Physiologic mechanisms of postischemic tissue injury. Annu Rev Physiol 57:311-332, 1995 7. Paller MS: Acute renal failure: Controversies, clinical trials, and future directions. Semin Nephrol 18:482-489, 1998 8. Harlan JM: Neutrophil-mediated vascular injury. Acta Med Scand Suppl 715:123-129, 1987 9. Weiss SJ: Tissue destruction by neutrophils. N Engl J Med 320:365-376, 1989 10. Ho¨rl WH, Schafer RM, Horl M, Heidland A: Neutrophil activation in acute renal failure and sepsis. Arch Surg 125:651-654, 1990 11. Jennette JC, Falk RJ: Acute renal failure secondary to leukocyte-mediated acute glomerular injury. Renal Failure 14:395-399, 1992

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