Is complement a target for therapy in renal disease?
1998; Elsevier BV; Volume: 54; Issue: 5 Linguagem: Inglês
10.1046/j.1523-1755.1998.00129.x
ISSN1523-1755
Autores Tópico(s)Hemoglobinopathies and Related Disorders
ResumoIs complement a target for therapy in renal disease? Complement deposition in the injured kidney is common, especially in glomerulonephritis. The precise role of the complement system in the mediation of tissue injury in the kidney has been defined in recent years, and this has assumed extra importance with the recent development of specific forms of therapy directed at the complement pathway. As well as the induction of cell lysis, complement has many subtle effects on cell biology, particularly on endothelial cells. Complement components are produced locally in the kidney. Detailed studies of certain rare forms of nephritis have provided evidence that complement activation can directly cause tissue injury. Appreciation of the importance of complement in hyperacute rejection of xenotransplants has given new impetus to the development of complement inhibitors. A narrative review is provided, with a brief overview of the complement pathway and its regulatory mechanisms, mechanisms of complement-induced tissue injury, local complement production, and the renal consequences of complement dysregulation. Currently available forms of therapy aimed at the complement system are reviewed, and possible future therapeutic strategies are suggested. The complement system plays a direct causal role in tissue injury in certain forms of renal disease. Specific forms of therapy are becoming available that can selectively interrupt complement activation or promote its regulation. Much of the drive for the development of these therapies comes from the field of xenotransplantation, but these forms of therapy should also be tested in various primary renal diseases. Is complement a target for therapy in renal disease? Complement deposition in the injured kidney is common, especially in glomerulonephritis. The precise role of the complement system in the mediation of tissue injury in the kidney has been defined in recent years, and this has assumed extra importance with the recent development of specific forms of therapy directed at the complement pathway. As well as the induction of cell lysis, complement has many subtle effects on cell biology, particularly on endothelial cells. Complement components are produced locally in the kidney. Detailed studies of certain rare forms of nephritis have provided evidence that complement activation can directly cause tissue injury. Appreciation of the importance of complement in hyperacute rejection of xenotransplants has given new impetus to the development of complement inhibitors. A narrative review is provided, with a brief overview of the complement pathway and its regulatory mechanisms, mechanisms of complement-induced tissue injury, local complement production, and the renal consequences of complement dysregulation. Currently available forms of therapy aimed at the complement system are reviewed, and possible future therapeutic strategies are suggested. The complement system plays a direct causal role in tissue injury in certain forms of renal disease. Specific forms of therapy are becoming available that can selectively interrupt complement activation or promote its regulation. Much of the drive for the development of these therapies comes from the field of xenotransplantation, but these forms of therapy should also be tested in various primary renal diseases. The complement pathway is a phylogenetically ancient system of interacting proteins that forms part of the host defence response. Complement has been of interest to nephrologists and renal pathologists ever since techniques of immunohistological analysis allowed the demonstration of complement components deposited in the kidney in certain forms of glomerulonephritis, associated in some cases with evidence of systemic complement activation. However, whether such evidence of local or systemic complement activation is causally related to tissue injury in the kidney, or merely an epiphenomenon, has remained controversial. This argument remained only of academic rather than clinical significance while there were no specific methods of achieving selective blockade of complement activation. Several recent advances have suggested that this is an area that deserves further attention from those interested in the pathogenesis and treatment of kidney disease. First, it has become apparent that complement is not only involved in the lysis of target cells. There are many more subtle effects on cell biology that can result from sublytic complement attack or as a response to the by-products of complement activation. Second, there has been an increasing appreciation that complement components are produced locally in a variety of tissues, and that this is particularly prominent in the kidney. Third, detailed studies of certain rare forms of nephritis have indicated that complement activation may play a direct causal role in tissue injury. Fourth, and perhaps most significant, is the recent development of novel therapeutic approaches aimed at preventing or limiting complement activation systemically or locally. The purpose of this article is to review some of these recent advances and attempt to assess their significance for nephrology. Over thirty proteins are involved in the three pathways of complement activation Figure 1, and many of these, some cell-bound and some secreted, have regulatory functions that impose tight control on complement activation. This complex regulatory machinery prevents unnecessary or excessive complement activation in health. The classical pathway is mainly activated by antigen/antibody complexes. This is the pathway responsible for the augmentation of the effector functions of antibodies and also is concerned with the effective handling of immune complexes by maintenance of their solubility, allowing their delivery to the reticulo-endothelial system for safe disposal. The alternative pathway is more concerned with host defence, being mainly activated by foreign surfaces such as microorganisms. It has two distinguishing features: activation is antibody-independent, and the pathway has a constant low-level of activation, existing in a state of so-called “tickover.” Therefore, regulation is critical to prevent excessive activity, and an understanding of this regulatory mechanism is crucial to the explanation of the dysregulated alternative pathway activation associated with some forms of renal disease, to be considered later. Regulatory mechanisms exist in the fluid phase and on the cell membrane, and these two groups of inhibitors work together to downregulate inappropriate complement activation. The rate-limiting enzyme is the alternative pathway C3 convertase, denoted C3bBb. This enzyme is unstable, having a half-life of only a few minutes in vivo. Its dissociation is promoted in the fluid phase by two regulatory proteins factor H and factor I, and on the cell membrane by decay accelerating factor (DAF). A recently described third pathway of complement activation is the lectin or mannan-binding protein pathway1.Matsushita M. Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel Cls-like serine protease.J Exp Med. 1992; 176: 1497-1502Crossref PubMed Scopus (531) Google Scholar, which has similar consequences to those of classical pathway activation. The relevance of this pathway to renal disease is not yet known. Activation of either the classical or alternative pathway leads to a final common pathway of complement activation, the terminal pathway. This culminates in the formation of the membrane attack complex (MAC or C5b-9), which when inserted in sufficient quantity into the plasma membrane of target cells leads to the formation of pores, entry of water and extracellular ions, cell swelling, and ultimately cell lysis. It has become apparent in recent years that C5b-9 also has other potent effects on the biology of target cells, and that sublytic complement activation may be an important phenomenon in vivo. Much of the work on this subject relates to endothelial cells, but other intrinsic renal cells such as mesangial cells or podocytes may be affected in a similar way. Production of C5b-9 on the endothelial cell surface has procoagulant and pro-inflammatory consequences, leading to rapid influx of calcium into the cell, secretion of Weibel-Palade bodies with release of procoagulant high molecular weight forms of von Willebrand factor, exposure of binding sites for factor Va, release of platelet activating factor that stimulates the adhesion and aggregation of platelets, and upregulation of the expression of GMP-140, a p-selectin that promotes the adherence of neutrophils2.Hattori R. Hamilton K.K. McEver R.P. Sims P.J. Complement proteins C5b-9 induce secretion of high molecular weight multimers of endothelial von Willebrand factor and translocation of granule membrane protein GMP-140 to the cell surface.J Biol Chem. 1989; 264: 9053-9060Abstract Full Text PDF PubMed Google Scholar. By-products of complement activation may further amplify the process. For example, C3a and C5a, by-products respectively of cleavage of C3 and C5 (by either pathway), act as anaphylatoxins that attract and activate leukocytes, recruiting them to the inflammatory focus. C5a also leads to the release of procoagulant heparan sulphate from endothelial cells3.Platt J.L. Vercellotti G.M. Lindman B.J. Oegema T.R. Bach F.H. Dalmasso A.P. Release of heparan sulfate from endothelial cells. Implications for pathogenesis of hyperacute rejection.J Exp Med. 1990; 171: 1363-1368Crossref PubMed Scopus (250) Google Scholar; deposition of iC3b, a ligand for the complement receptor CR3 on neutrophils, on the endothelial cell surface will further promote the accumulation of inflammatory leukocytes4.Marks R.M. Todd R.F. Ward P.A. Rapid induction of neutrophil-endothelial adhesion by endothelial complement fixation.Nature. 1989; 339: 314-317Crossref PubMed Scopus (126) Google Scholar. Complement activation also has effects on platelets, with calcium-dependent activation of protein kinases leading to secretion of procoagulant molecules from storage granules5.Sims P.J. Interaction of human platelets with the complement system.in: Kunicki T.J. George J.N. Platelet Immunobiology, Molecular and Clinical Aspects. J.B. Lippincott, Philadelphia1989: 354-383Google Scholar. Thus, the net result of complement activation on platelet-endothelial interactions is a shift towards a more procoagulant state. Sublytic C5b-9 also has potent pro-inflammatory effects on mesangial cells in vitro6.Adler S. Baker P.J. Johnson R.J. Ochi R.F. Pritzl P. Couser W.G. Complement membrane attack complex stimulates production of oxygen metabolites by cultured rat mesangial cells.J Clin Invest. 1986; 77: 762-777Crossref PubMed Scopus (183) Google Scholar,7.Schonermark M. Deppisch R. Riedasch G. Rother K. Hansch G.M. Induction of mediator release from human glomerular mesangial cells by the terminal complement components C5b-9.Int Archs Allergy Appl Immunol. 1991; 96: 331-337Crossref PubMed Scopus (57) Google Scholar. The recent demonstration that human mesangial cells have receptors for the anaphylatoxin C5a, and that binding of C5a to mesangial cells induces upregulation of transcription factors and early response genes8.Wilmer W.A. Kaumaya P.T. Ember J.A. Cosio F.G. Receptors for the anaphylatoxin C5a (CD88) on human mesangial cells.J Immunol. 1998; 160: 5646-5652PubMed Google Scholar, illustrates a novel mechanism whereby complement activation may directly influence resident cells in the kidney, in addition to the pro-inflammatory effects mediated via leukocyte attraction. It has been known for many years that complement influences the afferent arm of an immune response. Complement-depleted mice are less able to mount an antibody response9.Pepys M.B. Role of complement in induction of antibody production in vivo.J Exp Med. 1974; 140: 126-145Crossref PubMed Scopus (265) Google Scholar. A mechanism for this is illustrated by recent work showing that C3d, a breakdown product of C3 and the ligand for complement receptor CR2, can act as an adjuvant: antigen tagged with C3d molecules was much more potent at eliciting an antibody response, presumably due to cross-linking of CR2 molecules on B lymphocytes10.Dempsey P.W. Allison M.E. Akkaraju S. Goodnow C.C. Fearon D.T. C3 days of complement as a molecular adjuvant: bridging innate and acquired immunity.Science. 1996; 271: 348-350Crossref PubMed Scopus (972) Google Scholar. Most complement components are produced in the liver, but local production in a number of organs is now well documented11.Morgan B.P. Gasque P. Extrahepatic complement biosynthesis: Where, when and why?.Clin Exp Immunol. 1997; 107: 1-7Crossref PubMed Scopus (230) Google Scholar. In the kidney this has been most clearly shown for C3 and C4, which are synthesized and secreted by renal tubular epithelial cells, mesangial cells and glomerular epithelial cells12.Sacks S.H. Zhou W. Sheerin N.S. Complement synthesis in the injured kidney: Does it have a role in immune complex glomerulonephritis?.J Am Soc Nephrol. 1996; 7: 2314-2319PubMed Google Scholar. This expression is upregulated by pro-inflammatory cytokines, and also in various forms of nephritis. Factor B is expressed in normal kidney, and possibly also factor D13.Peake P.W. Cheng H. Charlesworth J.A. Pussell B.A. Presence of an intact alternative pathway of complement in the human kidney. (abstract).Nephrol. 1997; 3: S236Google Scholar,14.Song D. Zhou W. Neil S. Sacks S.H. Compartmental localisation of complement component transcripts in the normal human kidney. (abstract).Nephrol. 1997; 3: S235Google Scholar. Complement regulatory molecules including decay accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46) are expressed in the kidney in health and disease15.Cosio F.G. Sedmak D.D. Mahan J.D. Nahman N.S. Localization of decay accelerating factor in normal and diseased kidneys.Kidney Int. 1989; 36: 100-107Abstract Full Text PDF PubMed Scopus (69) Google Scholar,16.Endoh M. Yamashina M. Ohi H. Funahashi K. Ikuno T. Yasugi T. Atkinson J.P. Okada H. Immunohistochemical demonstration of membrane cofactor protein (MCP) of complement in normal and diseased kidney tissues.Clin Exp Immunol. 1993; 94: 182-188Crossref PubMed Scopus (47) Google Scholar. Another tissue capable of local production of complement components is the vascular endothelium. Endothelial cells lie at the interface between the tissues and the circulation, and complement activation on the endothelial surface is a common feature in many forms of tissue injury. As with other tissues, the relative contributions of locally produced complement and circulating complement remain to be determined. Certainly the local expression of regulators of complement activation makes teleological sense, since there may be a need to control complement activation at this site. Endothelial cells abundantly express membrane-bound regulators of complement activation such as CD59, MCP and DAF, and this underlies the strategy for prevention of hyperacute xenograft rejection by transgenic expression of the human versions of these regulators in pigs [reviewed in17.Mathieson P.W. Fearon D.T. Moore Jr, F.D. Tilney N.L. Strom T.B. Paul L.C. Transplantation Biology: Cellular and Molecular Aspects. Lippincott-Raven Publishers, Philadelphia1996: 163-173Google Scholar]. Factor H, important in regulation of the alternative pathway, is also expressed by endothelial cells. Intriguingly, pro-inflammatory cytokines (which enhance endothelial synthesis of C3 and factor B) lead to downregulation of factor H, tipping the balance in favor of activation, presumably as a defence mechanism18.Coulpier M. Andreev S. Lemercier C. Dauchel H. Lees O. Fontaine M. Ripoche J. Activation of the endothelium by IL-1α and glucocorticoids results in major increase of complement C3 and factor B production and generation of C3a.Clin Exp Immunol. 1995; 101: 142-149Crossref PubMed Scopus (33) Google Scholar. Hemolytic-uremic syndrome (HUS) is characterized by marked endothelial injury, especially in the kidney, and it is therefore fascinating that defective complement regulation may predispose to this condition. This is considered further in the next section. As mentioned earlier, tight regulatory mechanisms exist to limit complement activation in health. For the alternative pathway, factor H is a key regulatory protein, and the consequences of loss of its regulatory effects are amply illustrated by study of individuals whose ability to produce this protein is deficient. This has been best studied in a variety of Yorkshire pig19.Hogasen K. Jansen J.H. Mollnes T.E. Hovdenes J. Harboe M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency.J Clin Invest. 1995; 95: 1054-1061Crossref PubMed Scopus (176) Google Scholar, but rare human cases have also been reported20.Levy M. Halbwachs-Mecarelli L. Gubler M.-C. Kohout G. Bensenouci A. Niaudet P. Hauptmann G. Lesavre P. H deficiency in two brothers with atypical dense intramembranous deposit disease.Kidney Int. 1986; 30: 949-956Abstract Full Text PDF PubMed Scopus (136) Google Scholar. In the pig, genetic factor H deficiency leads to the development of glomerulonephritis (GN), with morphological appearances directly analogous to mesangiocapillary GN type II in humans (also known as membranoproliferative GN type II or dense deposit disease), which leads to the rapid development of renal failure and death from uremia19.Hogasen K. Jansen J.H. Mollnes T.E. Hovdenes J. Harboe M. Hereditary porcine membranoproliferative glomerulonephritis type II is caused by factor H deficiency.J Clin Invest. 1995; 95: 1054-1061Crossref PubMed Scopus (176) Google Scholar. The pigs have evidence of unregulated systemic alternative pathway activation, and importantly it has recently been shown that administration of exogenous factor H is an effective therapy, even if treatment is not started until after GN is established21.Hogasen K. Jansen J.H. Porcine membranoproliferative glomerulonephritis (MPGN) type II is reversed by factor H substitution therapy. (abstract).J Am Soc Nephrol. 1997; 8: 474A-475AGoogle Scholar. These animals prove that alternative pathway dysregulation alone can cause nephritis, and that restoration of the capacity to regulate the alternative pathway is sufficient to restore health. In humans, genetic factor H deficiency may also lead to MCGN20.Levy M. Halbwachs-Mecarelli L. Gubler M.-C. Kohout G. Bensenouci A. Niaudet P. Hauptmann G. Lesavre P. H deficiency in two brothers with atypical dense intramembranous deposit disease.Kidney Int. 1986; 30: 949-956Abstract Full Text PDF PubMed Scopus (136) Google Scholar, and the molecular basis of the defect has recently been characterized in one such patient. Mutations leading to loss of cysteine residues altered the protein structure in such a way that intracellular processing of factor H was disrupted22.Ault B.H. Schmidt B.Z. Fowler N.L. Kashtan C.E. Ahmed A.E. Vogt B.A. Colten H.R. Human factor H deficiency–Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism.J Biol Chem. 1997; 272: 25168-25175Crossref PubMed Scopus (123) Google Scholar. The importance of functional factor H is further illustrated by a case report of an individual whose serum contained a monoclonal lambda light chain that interacted with factor H in vitro and prevented its action, allowing unregulated alternative pathway activation. That patient also developed type II MCGN23.Meri S. Koistinen V. Miettinen A. Tornroth T. Seppala I.J.T. Activation of the alternative pathway of complement by monoclonal lambda light chains in membranoproliferative glomerulonephritis.J Exp Med. 1992; 175: 939-950Crossref PubMed Scopus (164) Google Scholar. Thus, disruption of the action of factor H by whatever mechanism can lead to MCGN. Another area of recent research should be mentioned that concerns HUS, a condition of great interest to nephrologists. One early report indicated that factor H deficiency might predispose to HUS24.Thompson R.A. Winterborn M.H. Hypocomplementaemia due to a genetic deficiency of β1H globulin.Clin Exp Immunol. 1981; 46: 110-119PubMed Google Scholar, and certainly complement activation is conspicuous in this condition25.Robson W.L. Leung A.K. Fick G.H. Mc Kenna A.I. Hypocomplementemia and leukocytosis in diarrhoea-associated hemolytic uremic syndrome.Nephron. 1992; 62: 296-299Crossref PubMed Scopus (65) Google Scholar. Rarely, recurrent HUS occurs in a familial form, and it has recently been reported that mutations of the factor H gene in these families are associated with unregulated complement activation and episodic HUS26.Warwicker P. Goodship T.H.J. Doune R.L. Pirson Y. Nicholls A. Ward R.M. Goodship J.A. Genetic studies into inherited and sporadic hemolytic uremic syndrome.Kidney Int. 1998; 53 (editorial, p 1085): 836-844Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar. The relevance of this to more common forms of HUS is not yet certain, but it is noteworthy that an abnormality of the factor H gene has been found in at least one individual with sporadic HUS26.Warwicker P. Goodship T.H.J. Doune R.L. Pirson Y. Nicholls A. Ward R.M. Goodship J.A. Genetic studies into inherited and sporadic hemolytic uremic syndrome.Kidney Int. 1998; 53 (editorial, p 1085): 836-844Abstract Full Text Full Text PDF PubMed Scopus (402) Google Scholar and that the factor H gene is polymorphic27.Day A.J. Willis A.C. Ripoche J. Sim R.B. Sequence polymorphism of human complement factor H.Immunogenetics. 1988; 27: 211-214Crossref PubMed Scopus (41) Google Scholar,28.Warwicker P. Goodship T.H.J. Goodship J.A. Three new polymorphisms in the human complement factor H gene and promoter region.Immunogenetics. 1997; 46: 437-438Crossref PubMed Scopus (22) Google Scholar, leading to the possibility that genetic variability at this locus could be associated with susceptibility to disease. Another situation in humans where unregulated alternative pathway activation is associated with MCGN is in the presence of nephritic factor (NeF), an IgG autoantibody that binds to a neoantigen formed when the alternative pathway C3 convertase enzyme, C3bBb, is assembled. The antibody stabilizes this enzyme and protects it from degradation by factor H. Thus, the half-life of the enzyme is prolonged and the normal regulatory mechanism is subverted. The close association between NeF and MCGN implies, but does not prove, causality29.Mathieson P.W. Peters D.K. Are nephritic factors nephritogenic?.Am J Kidney Dis. 1994; 24: 964-966Abstract Full Text PDF PubMed Scopus (12) Google Scholar. However, the fact that similar renal injury arises when the alternative pathway is dysregulated by the other mechanisms outlined above, namely factor H deficiency or dysfunction, strongly implies that it is the complement activation per se which induces the nephritis. The other clinical condition associated with NeF, with or without coexisting nephritis, is partial lipodystrophy (PLD) in which there is loss of adipose tissue from the face, arms and upper trunk30.Sissons J.G.P. West R.J. Fallows J. Williams D.G. Boucher B.J. Amos N. Peters D.K. The complement abnormalities of lipodystrophy.N Engl J Med. 1976; 294: 461-465Crossref PubMed Scopus (202) Google Scholar. Adipocytes are another abundant source of local complement production, particularly of factor D, which plays a central role in normal adipose tissue regulation [reviewed in31.Mathieson P.W. Peters D.K. Lipodystrophy in MCGN type II: The clue to links between the adipocyte and the complement system.Nephrol Dial Transplant. 1997; 12: 1804-1806Crossref PubMed Scopus (32) Google Scholar]. We have reported that NeF-containing serum or IgG, but not normal or disease-control sera/IgG, could induce complement-dependent lysis of adipocytes in vitro32.Mathieson P.W. Würzner R. Oliveira D.B.G. Lachmann P.J. Peters D.K. Complement-mediated adipocyte lysis by nephritic factor sera.J Exp Med. 1993; 177: 1827-1831Crossref PubMed Scopus (84) Google Scholar,33.Mathieson P.W. Prins J. Würzner R. Oliveira D.B.G. Lachmann P.J. Peters D.K. Nephritic factor and complement-mediated lysis of adipocytes. (abstract).Q J Med. 1994; 87: 584Google Scholar. Furthermore, there are regional variations in levels of expression of factor D that mirror the distribution of fat cell loss in PLD, the higher levels being found in fat from the face and upper trunk33.Mathieson P.W. Prins J. Würzner R. Oliveira D.B.G. Lachmann P.J. Peters D.K. Nephritic factor and complement-mediated lysis of adipocytes. (abstract).Q J Med. 1994; 87: 584Google Scholar. Thus, NeF appears capable of directly causing adipocyte destruction, and the level of production of factor D by adipocytes may determine their susceptibility to injury by NeF. Since intrinsic renal cells express an array of complement proteins similar to those expressed by adipocytes, the obvious implication is that NeF may directly injure renal cells in an analogous manner. As yet there is no direct evidence for this action, but a recent report showed that alternative pathway activation can injure renal tubular epithelial cells34.David S. Biancone L. Caserta C. Bussolati B. Cambi V. Camussi G. Alternative pathway complement activation induces proinflammatory activity in human proximal tubular cells.Nephrol Dial Transplant. 1997; 12: 51-56Crossref PubMed Scopus (4) Google Scholar. Lupus nephritis is the archetypal immune complex nephritis, where complement activation in the glomerulus is assumed to be important, and therapy aimed at complement has been advocated. Intriguingly, a very recent report in a murine model of lupus strongly suggests that Fc receptor-mediated mechanisms of inflammation are more important that those involving complement35.Clynes R. Dumitru C. Ravetch J.V. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis.Science. 1998; 279: 1052-1054Crossref PubMed Scopus (506) Google Scholar. The importance of complement in renal disease is not, however, confined to rare esoteric forms of glomerulonephritis as complement activation may play an important role in other, more common forms of renal injury. For example, there is a wealth of evidence for a vital role of complement in ischemia-reperfusion injury. This is important to nephrologists in the context of transplantation, after revascularization for renovascular disease, and possibly also in some forms of ischemic acute renal failure. Complement inhibition provides substantial protection against this form of injury36.Weisman H.F. Bartow T. Leppo M.K. Marsh Jr, H.C. Carson G.R. Concino M.F. Boyle M.P. Roux K.H. Weisfeldt M.L. Fearon D.T. Soluble human complement receptor type 1: In vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis.Science. 1990; 249: 146-151Crossref PubMed Scopus (844) Google Scholar, 37.Hill J. Lindsay T.F. Ortiz F. Yeh C.G. Hechtman H.B. Moore F.D. Soluble complement receptor type 1 ameliorates the local and remote organ injury after intestinal ischemia-reperfusion in the rat.J Immunol. 1992; 149: 1723-1728PubMed Google Scholar, 38.Pemberton M. Anderson G. Vetvicka V. Justus D.E. Ross G.D. Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle.J Immunol. 1993; 150: 5104-5113PubMed Google Scholar, probably by inhibiting leukocyte attraction and infiltration38.Pemberton M. Anderson G. Vetvicka V. Justus D.E. Ross G.D. Microvascular effects of complement blockade with soluble recombinant CR1 on ischemia/reperfusion injury of skeletal muscle.J Immunol. 1993; 150: 5104-5113PubMed Google Scholar. Another important and possibly underestimated cause of renal injury is embolization of material from atheromatous plaques39.Cosio F.G. Zager R.A. Sharma H.M. Atheroembolic renal disease causes hypocomplementaemia.Lancet. 1985; ii: 118-121Abstract Scopus (111) Google Scholar. One feature of the syndrome associated with cholesterol emboli is systemic complement activation leading to hypocomplementemia40.Case Records of the Massachusetts General Hospital: Case 34–1991. N Engl J Med. 1991; 325: 563-572Crossref Scopus (20) Google Scholar, and it has been shown that components of atheroma are potent activators of complement41.Seifert P.S. Messner M. Roth I. Bhakdi S. Analysis of complement C3 activation products in human atherosclerotic lesions.Atherosclerosis. 1991; 91: 155-162Abstract Full Text PDF PubMed Scopus (14) Google Scholar,42.Seifert P.S. Hugo F. Tranum-Jensen J. Zahringer U. Muhly M. Bhakdi S. Isolation and characterization of a complement-activating lipid extracted from human atherosclerotic lesions.J Exp Med. 1990; 172: 547-557Crossref PubMed Scopus (121) Google Scholar. The therapeutic potential of complement inhibition in patients suspected of having this form of renal injury may be considerable but as yet remain unexplored. Indeed, complement may be involved in atherosclerosis itself. The inflammatory nature of atherosclerotic vascular disease is increasingly being appreciated. In one experimental model, deposition of C5b-9 was one of the earliest histological manifestations, preceding monocyte infiltration and foam cell development43.Seifert P.S. Hugo F. Hansson G.K. Bhakdi S. Prelesional complement activation in experimental atherosclerosis.Lab Invest. 1989; 60: 747-754PubMed Google Scholar, indicating that the terminal complement pathway is likely to be involved in atheroma development and that measures aimed at complement inhibition may have therapeutic potential in atherosclerosis. There may be implications for the role of complement in chronic allograft rejection, elements of which have similarities to atherosclerosis44.Mennander A. Tiisala S. P
Referência(s)