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Endothelial injury and dysfunction: Role in the extension phase of acute renal failure

2004; Elsevier BV; Volume: 66; Issue: 2 Linguagem: Inglês

10.1111/j.1523-1755.2004.761_5.x

1523-1755

Bruce A. Molitoris, Timothy A. Sutton,

Renal and Vascular Pathologies

Endothelial injury and dysfunction: Role in the extension phase of acute renal failure. The pathophysiology of ischemic acute renal failure (ARF) involves a complex interplay between renal hemodynamics, tubular and endothelial cell injury, and inflammatory processes. A growing body of evidence supports the contribution of altered renal vascular function, especially at the microvascular level, in initiating and subsequently extending the initial tubular injury. The extension phase of ischemic ARF involves continued reduction in renal perfusion, ongoing hypoxia, and inflammatory processes that occur during reperfusion and contribute to continued tubular cell injury. Vascular endothelial cell injury and dysfunction play a vital part in this extension phase. With injury, the endothelial cell loses its ability to regulate vascular tone, perfusion, permeability and inflammation/adhesion. This loss of regulatory function has a detrimental impact upon renal function. Vascular congestion, edema formation, diminished blood flow, and infiltration of inflammatory cells have been documented in the corticomedullary junction of the kidney. However, linking their genesis to microvascular endothelial injury and dysfunction has been difficult. New diagnostic and therapeutic approaches to ischemic ARF must incorporate these finding to devise early recognition strategies and therapeutic approaches. Endothelial injury and dysfunction: Role in the extension phase of acute renal failure. The pathophysiology of ischemic acute renal failure (ARF) involves a complex interplay between renal hemodynamics, tubular and endothelial cell injury, and inflammatory processes. A growing body of evidence supports the contribution of altered renal vascular function, especially at the microvascular level, in initiating and subsequently extending the initial tubular injury. The extension phase of ischemic ARF involves continued reduction in renal perfusion, ongoing hypoxia, and inflammatory processes that occur during reperfusion and contribute to continued tubular cell injury. Vascular endothelial cell injury and dysfunction play a vital part in this extension phase. With injury, the endothelial cell loses its ability to regulate vascular tone, perfusion, permeability and inflammation/adhesion. This loss of regulatory function has a detrimental impact upon renal function. Vascular congestion, edema formation, diminished blood flow, and infiltration of inflammatory cells have been documented in the corticomedullary junction of the kidney. However, linking their genesis to microvascular endothelial injury and dysfunction has been difficult. New diagnostic and therapeutic approaches to ischemic ARF must incorporate these finding to devise early recognition strategies and therapeutic approaches. The cellular and molecular events involved in ischemic acute renal failure (ARF) have been identified and a much more complete understanding of how these events result in cellular and organ dysfunction has been established. Growing evidence indicates renal vascular endothelial injury and dysfunction play an important part in initiating and extending renal tubular epithelial injury and thus contribute to the ongoing pathogenesis of ischemic ARF. In fact, what is becoming rapidly apparent is that the lack of adequate renal cortical-medullary reperfusion may be more deleterious than the classical “reperfusion injury” secondary to oxygen and nitrogenous free radical formation. Therefore, the purpose of this review is to summarize what is known about endothelial injury/dysfunction during and following ischemia in the kidney, and to place these data into a unifying hypothesis regarding immediate and delayed epithelial cell injury and organ dysfunction. Finally, how therapy of ARF should take into account the pathophysiology of endothelial dysfunction will be discussed. The concept of the endothelium as an organ has become widely appreciated1.Hack C.E. Zeerleder S. The endothelium in sepsis: Source of and a target for inflammation.Crit Care Med. 2001; 29: S21-S27Crossref PubMed Scopus (232) Google Scholar given the recent recognition of the consequences of endothelial injury and dysfunction in a range of disease states such as sepsis, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), diabetes, and hypertension. The endothelium regulates vascular permeability and modulates vasomotor, inflammatory, and hemostatic responses. Impairment of these vital endothelial cell functions during and following renal ischemia can contribute to the impairment of renal perfusion, continued renal hypoxia, and the subsequent epithelial cell injury and diminution in glomerular filtration rate (GFR) that are the hallmarks of ARF. Endothelial cells in different vascular beds have different characteristics2.Stevens T. Rosenberg R. Aird W. et al.NHLBI workshop report: Endothelial cell phonotypes in heart, lung, and blood diseases.Am J Physiol Cell Physiol. 2001; 281: C1422-C1433PubMed Google Scholar. Therefore, as the environment within the kidney changes dramatically from the outer cortex to the medullary region, endothelial cells may differ considerably within the kidney from region to region. The extension phase of ischemic ARF is ushered in by two major events: (1) continued hypoxia following the initial ischemic event and (2) an inflammatory response3.Sutton T.A. Fisher C.J. Molitoris B.A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure.Kidney Int. 2002; 62: 1539-1549Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar. Both events are more pronounced in the corticomedullary junction (CMJ), or outer medullary region, of the kidney. Documentation of severely reduced blood flow, stasis, and accumulation of red blood cells and white blood cells has been historically noted; however, the epithelial ramifications of these events have only recently been uncovered4.Rabb H. O'Meara Y.M. Maderna P. et al.Leukocytes, cell adhesion molecules and ischemic acute renal failure.Kidney Int. 1997; 51: 1463-1468Abstract Full Text PDF PubMed Scopus (254) Google Scholar,5.Linas S. Whittenburg D. Repine J.E. Nitric oxide prevents neutrophil-mediated acute renal failure.Am J Physiol. 1997; 272: F48-F54PubMed Google Scholar. It is during this phase that renal vascular endothelial cell damage likely plays a key role in the continued ischemia of the renal tubular epithelium, as well as, the inflammatory response observed with ischemic ARF. During this phase, S3 proximal tubule and thick ascending limb cells, as well as endothelial cells, continue to undergo injury and death with both necrosis and apoptosis being present predominantly in the outer medulla6.Kelly K.J. Plotkin Z. Dagher P.C. Guanosine supplementation reduces apoptosis and protects renal function in the setting of ischemic injury.J Clin Invest. 2001; 108: 1291-1298Crossref PubMed Scopus (125) Google Scholar. In contrast, the proximal tubule cells in the outer cortex, where blood flow has returned to near normal levels, undergo cellular repair and improve morphologically during this phase. As cellular injury continues in the CMJ region during the extension phase, the GFR continues to fall. There is continued production and release of chemokines and cytokines that further enhance the inflammatory cascade. A decrease in renal blood flow is of critical importance in initiating and extending the pathophysiology of ischemic ARF. Under physiologic conditions, the oxygen tension of the kidney decreases as one moves from the outer cortex to the inner medulla7.Brezis M. Rosen S. Hypoxia of the renal medulla—Its implications for disease.N Engl J Med. 1995; 332: 647-655Crossref PubMed Scopus (895) Google Scholar. Regional alterations in renal blood flow persist after the initial ischemic event and play an important role in the extension phase of renal ischemic injury. During reperfusion a reduction in total renal blood flow of 40% to 50% of normal has been reported in both animal models of ischemic ARF and in human ischemic ARF8.Lieberthal W. Biology of acute renal failure: Therapeutic implications.Kidney Int. 1997; 52: 1102-1115Abstract Full Text PDF PubMed Scopus (63) Google Scholar. Studies have demonstrated a persistent reduction in renal blood flow contributes significantly to the diminished GFR observed in human renal allografts following ischemic ARF9.Alejandro V. Scandling Jr, J.D. Sibley R.K. et al.Mechanisms of filtration failure during postischemic injury of the human kidney. A study of the reperfused renal allograft.J Clin Invest. 1995; 95: 820-831Crossref PubMed Google Scholar. These persistent perfusion deficits have been demonstrated to be of greater magnitude in the outer medulla than in the outer cortex or inner medulla in an animal model of ischemic ARF10.Olof P. Hellberg A. Kallskog O. Wolgast M. Red cell trapping and postischemic renal blood flow. Differences between the cortex, outer and inner medulla.Kidney Int. 1991; 40: 625-631Abstract Full Text PDF PubMed Scopus (87) Google Scholar,11.Mason J. Torhorst J. Welsch J. Role of the medullary perfusion defect in the pathogenesis of ischemic renal failure.Kidney Int. 1984; 26: 283-293Abstract Full Text PDF PubMed Scopus (100) Google Scholar. Mechanisms involved in the alteration of renal perfusion following ischemic injury are incompletely understood. An imbalance between mediators of renal vasoconstriction and renal vasodilatation has been proposed to play a role in animal models of ischemic ARF. In support of this, antagonists to endogenous vasoconstrictors have been shown to ameliorate renal ischemic injury in animal models12.Chan L. Chittinandana A. Shapiro J.I. et al.Effect of an endothelin-receptor antagonist on ischemic acute renal failure.Am J Physiol. 1994; 266: F135-F138PubMed Google Scholar, 13.Gellai M. Jugus M. Fletcher T. et al.Reversal of postischemic acute renal failure with a selective endothelinA receptor antagonist in the rat.J Clin Invest. 1994; 93: 900-906Crossref PubMed Google Scholar, 14.Kelly K.J. Tolkoff-rUBIN N.E. Rubin R.H. et al.An oral platelet-activating factor antagonist, Ro-24–4736, protects the rat kidney from ischemic injury.Am J Physiol. 1996; 271: F1061-F1067PubMed Google Scholar. The role various vasoreactive mediators may play in controlling renal vascular tone following ischemic injury has been the subject of a recent review15.Conger J. Vascular alterations in ARF: Roles in initiation and maintenance,.in: Molitoris B.A. Finn W.F. Acute Renal failure: A Companion to Brenner and Rector's The Kidney. Saunders, Philadelphia2001: 13-29Google Scholar. Congestion of the renal microcirculation, especially in the peritubular capillaries of the outer medullary region (vasa recta), contributes to deficits in renal perfusion. Accumulation of red blood cells and leukocytes in the outer medulla has been demonstrated in animal models of ischemic ARF as well as in human ischemic ARF10.Olof P. Hellberg A. Kallskog O. Wolgast M. Red cell trapping and postischemic renal blood flow. Differences between the cortex, outer and inner medulla.Kidney Int. 1991; 40: 625-631Abstract Full Text PDF PubMed Scopus (87) Google Scholar, 16.Hellberg P.O. Kallskog O. Wolgast M. 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Experimental maneuvers to diminish trapping of red blood cells and leukocyte attachment in the renal microcirculation have been demonstrated to improve morphologic and functional aspects of renal injury in animal models of ischemic ARF14.Kelly K.J. Tolkoff-rUBIN N.E. Rubin R.H. et al.An oral platelet-activating factor antagonist, Ro-24–4736, protects the rat kidney from ischemic injury.Am J Physiol. 1996; 271: F1061-F1067PubMed Google Scholar, 19.Rabb H. Mendiola C.C. Dietz J. et al.Role of CD11a and CD11b in ischemic acute renal failure in rats.Am J Physiol. 1994; 267: F1052-F1058PubMed Google Scholar, 20.Takada M. Nadeau K.C. Shaw G.D. et al.The cytokine-adhesion molecule cascade in ischemia/reperfusion injury of the rat kidney. Inhibition by a soluble P-selectin ligand.J Clin Invest. 1997; 99: 2682-2690Crossref PubMed Scopus (455) Google Scholar, 21.Hellberg P.O. Kallskog O.T. Ojteg G. Wolgast M. Peritubular capillary permeability and intravascular RBC aggregation after ischemia: Effects of neutrophils.Am J Physiol. 1990; 258: F1018-F1025PubMed Google Scholar, 22.Hellberg P.O. Bayati A. Kallskog O. Wolgast M. Red cell trapping after ischemia and long-term kidney damage. Influence of hematocrit.Kidney Int. 1990; 37: 1240-1247Abstract Full Text PDF PubMed Scopus (42) Google Scholar. Interestingly, no consistent morphologic changes of the renal vascular endothelium in ischemic ARF have been reported. In part this may be due to sampling bias in human ischemic ARF (i.e., predominantly cortical vs. medullary tissue on biopsy) and difficulty in visualizing the endothelium of potentially affected microvasculature in animal models. However, Sutton et al23.Sutton T.A. Mang H.E. Campos S.B. et al.Injury of the renal microvascular endothelium alters barrier function after ischemia.Am J Physiol Renal Physiol. 2003; 285: F191-F198Crossref PubMed Scopus (248) Google Scholar, using TIE2/GFP mice with selective endothelial cell expression of GFP, have shown actin cytoskeletal and junctional alterations occur in renal microvascular endothelial cells during ischemic injury in vivo. Evidence of endothelial dysfunction and injury in other organ systems, as a result of ischemic injury, lends credence to the concept that endothelial dysfunction and injury play an important role in ischemic ARF. Separation of endothelial tight junctions, loss of endothelial attachment to the basement membrane, endothelial blebbing, and endothelial necrosis have been described in the cerebral and coronary vasculature following ischemic injury24.Pomfy M. Huska J. The state of the microcirculatory bed after total ischaemia of the brain. An experimental ultrastructural study.Funct Dev Morphol. 1992; 2: 253-258PubMed Google Scholar,25.van der pOLL T. van dEVENTER S.J. Cytokines and anticytokines in the pathogenesis of sepsis.Infect Dis Clin North Am. 1999; 13: 413-426Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar. In patients experiencing septic shock, a condition which shares many pathologic derangements with ischemic injury and is often a concomitant condition in human ischemic ARF26.Solez K. Morel-mAROGER L. Sraer J.D. The morphology of “acute tubular necrosis” in man: analysis of 57 renal biopsies and a comparison with the glycerol model.Medicine (Baltimore). 1979; 58: 362-376Crossref PubMed Scopus (361) Google Scholar, detached, circulating endothelial cells have been documented27.Mutunga M. Fulton B. Bullock R. et al.Circulating endothelial cells in patients with septic shock.Am J Respir Crit Care Med. 2001; 163: 195-200Crossref PubMed Scopus (206) Google Scholar. Potential functional consequences of these morphologic alterations include altered vascular reactivity, increased vascular permeability, increased leukocyte adherence and extravasation, and altered coagulation due to loss of normal endothelial function and/or barrier. Furthermore, circulating activated endothelial cells could potentially contribute to distant organ effects often attributed to leukocytes, such as pulmonary dysfunction following ischemic ARF28.Kramer A.A. Postler G. Salhab K.F. et al.Renal ischemia/reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability.Kidney Int. 1999; 55: 2362-2367Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar. Increased renal peritubular capillary permeability has been documented as a consequence of ischemic ARF in animal models21.Hellberg P.O. Kallskog O.T. Ojteg G. Wolgast M. Peritubular capillary permeability and intravascular RBC aggregation after ischemia: Effects of neutrophils.Am J Physiol. 1990; 258: F1018-F1025PubMed Google Scholar, 22.Hellberg P.O. Bayati A. Kallskog O. Wolgast M. Red cell trapping after ischemia and long-term kidney damage. Influence of hematocrit.Kidney Int. 1990; 37: 1240-1247Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 23.Sutton T.A. Mang H.E. Campos S.B. et al.Injury of the renal microvascular endothelium alters barrier function after ischemia.Am J Physiol Renal Physiol. 2003; 285: F191-F198Crossref PubMed Scopus (248) Google Scholar. Two general mechanisms can account for increased endothelial permeability during ischemic injury: (1) increased paracellular permeability and/or (2) increased transcellular permeability29.Stevens T. Garcia J.G. Shasby D.M. et al.Mechanisms regulating endothelial cell barrier function.Am J Physiol Lung Cell Mol Physiol. 2000; 279: L419-L422PubMed Google Scholar. Increased interstitial edema may contribute to further diminishing the compromised medullary blood flow by compressing peritubular capillaries30.Klingebiel T. von gISE H. Bohle A. Morphometric studies on acute renal failure in humans during the oligoanuric and polyuric phases.Clin Nephrol. 1983; 20: 1-10PubMed Google Scholar. Additionally, leakage of plasma from the vascular space through a leaky endothelium contributes to hemoconcentration that can lead to stasis and diminished perfusion in the CMJ as observed in other organs31.Vollmar B. Glasz J. Leiderer R. et al.Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion.Am J Pathol. 1994; 145: 1421-1431PubMed Google Scholar. Hemoconcentration and stasis also increases the potential for endothelial-leukocyte interactions. Activated leukocytes can initiate an inflammatory cascade that leads to further endothelial cell injury and further dysfunction of the endothelial permeability barrier32.Kelly K.J. Molitoris B.A. Acute renal failure in the new millennium: Time to consider combination therapy.Semin Nephrol. 2000; 20: 4-19PubMed Google Scholar. This may be particularly important in the medullary region as endothelial cells there, but not in the cortex, express surface markers important in lymphocyte activation33.Kinjo T. Takashi M. Miyake K. Nagura H. Phenotypic heterogeneity of vascular endothelial cells in the human kidney.Cell Tissue Res. 1989; 256: 27-34Crossref PubMed Scopus (32) Google Scholar. Endothelial-leukocyte interactions mediated through complementary adhesion molecules on endothelial cells and leukocytes play a key role in the local accumulation of leukocytes. Ischemic injury has been demonstrated to increase expression of P- and E-selectin on the surface of endothelial cells34.Eppihimer M.J. Russell J. Anderson D.C. et al.Modulation of P-selectin expression in the postischemic intestinal microvasculature.Am J Physiol. 1997; 273: G1326-G1332PubMed Google Scholar,35.Molitoris B.A. Marrs J. The role of cell adhesion molecules in ischemic acute renal failure.Am J Med. 1999; 106: 583-592Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar. Increased expression of intercellular adhesion molecule-1 (ICAM-1) by endothelial cells has also been demonstrated in vitro in response to oxidant injury36.Ichikawa H. Flores S. Kvietys P.R. et al.Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells.Circ Res. 1997; 81: 922-931Crossref PubMed Scopus (169) Google Scholar. 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Nitric oxide prevents neutrophil-mediated acute renal failure.Am J Physiol. 1997; 272: F48-F54PubMed Google Scholar,38.Brodsky S.V. Yamamoto T. Tada T. et al.Endothelial dysfunction in ischemic acute renal failure: Rescue by transplanted endothelial cells.Am J Physiol Renal Physiol. 2002; 282: F1140-F1149Crossref PubMed Scopus (246) Google Scholar. Fibrin deposition in the microvasculature following ischemic injury has been noted in a variety of organs systems, including the kidney39.Enestrom S. Druid H. Rammer L. Fibrin deposition in the kidney in post-ischaemic renal damage.Br J Exp Pathol. 1988; 69: 387-394PubMed Google Scholar. Although the constitutive state of endothelial cells is an anticoagulant state, injury and activation of endothelial cells can induce a procoagulant response. Whether or not this occurs during prerenal azotmia is unknown. Furthermore, loss of nitric oxide production by injured endothelial cells may also contribute to an overall procoagulant state through loss of its inhibitory role on cytokine-induced expression of tissue factor40.Yang Y. Loscalzo J. Regulation of tissue factor expression in human microvascular endothelial cells by nitric oxide.Circulation. 2000; 101: 2144-2148Crossref PubMed Scopus (124) Google Scholar. While abnormalities in coagulation per se may have a deleterious role in ischemic ARF, recent studies have shed light on the relative importance the coagulation cascade plays as a mediator of inflammation in ischemic ARF41.Ozden A. Sarioglu A. Demirkan N.C. et al.Antithrombin III reduces renal ischemia-reperfusion injury in rats.Res Exp Med (Berlin). 2001; 200: 195-203PubMed Google Scholar,42.Mizutani A. Okajima K. Uchiba M. Noguchi T. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation.Blood. 2000; 95: 3781-3787Crossref PubMed Google Scholar. Recent advances made toward delineating the cellular mechanisms involved ischemic ARF have not yet lead to accepted therapeutic interventions that alter the natural course of ARF or improve the clinical outcome for ARF43.Liano F. Pascual J. Outcomes in acute renal failure.Semin Nephrol. 1998; 18: 541-550PubMed Google Scholar. Reviews outlining potential therapeutic strategies for the treatment of ARF, and the barriers minimizing effective therapies, have been recently published32.Kelly K.J. Molitoris B.A. Acute renal failure in the new millennium: Time to consider combination therapy.Semin Nephrol. 2000; 20: 4-19PubMed Google Scholar,44.Star R.A. Treatment of acute renal failure.Kidney Int. 1998; 54: 1817-1831Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar. Human ARF is heterogeneous in its pathophysiology. Consequently, combined therapies targeting more than one pathophysiologic pathway may prove to be the most beneficial approach32.Kelly K.J. Molitoris B.A. Acute renal failure in the new millennium: Time to consider combination therapy.Semin Nephrol. 2000; 20: 4-19PubMed Google Scholar,44.Star R.A. Treatment of acute renal failure.Kidney Int. 1998; 54: 1817-1831Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar. It is also necessary to point out that differences may exist between animal models of ARF and what has been documented to occur during human ARF45.Rosen S. Heyman S.N. Difficulties in understanding human “acute tubular necrosis”: Limited data and flawed animal models.Kidney Int. 2001; 60: 1220-1224Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar,46.Lieberthal W. Nigam S.K. Acute renal failure. II. Experimental models of acute renal failure: Imperfect but indispensable.Am J Physiol Renal Physiol. 2000; 278: F1-F12PubMed Google Scholar. However, a major problem is the lack of clinical biopsy data, especially in the CMJ area, during the early phases, initiation and extension, of human ARF. This has limited the ability to directly compare human and animal models of ischemic ARF. Therapies directed at processes during the extension phase, including endothelial dysfunction/injury, and its myriad of pathophysiologic implications, should have a role in any therapeutic approach. Interrupting the amplification of this hypoxic and inflammatory cascade has important therapeutic implications. Therefore, early recognition of renal injury and prompt intervention remain important clinical challenges in this field47.Molitoris B.A. Transitioning to therapy in ischemic acute renal failure.J Am Soc Nephrol. 2003; 14: 265-267Crossref PubMed Scopus (91) Google Scholar. A growing body of evidence lends support to the role endothelial dysfunction plays in overall renal injury during ischemic ARF. This may be especially important during the early events of ischemic ARF. Given that the endothelium is central to the myriad of biologic processes performed by the microvasculature, endothelial injury and dysfunction are crucial factors in the overall alteration of vascular function during both the initiation and the extension phase. Further investigation into the mechanisms of endothelial injury and dysfunction during the extension phase should provide further insight into the pathophysiology of ischemic ARF and reveal additional, as well as, novel therapeutic interventions.