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| __NOTOC__
| | #Redirect[[Nephritic syndrome#Pathophysiology]] |
| {{Nephritic syndrome}}
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| {{CMG}}; {{AE}} [[User:YazanDaaboul|Yazan Daaboul]], [[User:Sergekorjian|Serge Korjian]]
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| ==Overview==
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| It is believed that [[glomerular]] inflammation requires the activation of both the humoral and the cell-mediated immune system. Various [[glomerular disease]] have different pathophysiology, but the final cellular changes, immunological activation, and renal scarring are shared outcomes.
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| ==Pathophysiology==
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| ===Role of Antibodies===
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| Immunological mechanisms mediated by [[antibodies]] are required in the pathogenesis of [[glomerulonephritis]]. [[Antibodies]] are thought to bind either intrinsic glomerular components or specific compounds with unique physiochemical features that are present surrounding the [[glomerulus]]. [[Type IV collagen]] is an intrinsic glomerular component involved in [[Goodpasture's syndrome]]; whereas [[histone]]-DNA complexes in [[systemic lupus erythematosus]] are not intrinsic compounds to the [[glomerulus]].<ref name="pmid9744974">{{cite journal| author=Hricik DE, Chung-Park M, Sedor JR|title=Glomerulonephritis. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 13 | pages= 888-99 |pmid=9744974 | doi=10.1056/NEJM199809243391306 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9744974 }} </ref><ref name="pmid8621555">{{cite journal| author=Kalluri R, Sun MJ, Hudson BG, Neilson EG| title=The Goodpasture autoantigen. Structural delineation of two immunologically privileged epitopes on alpha3(IV) chain of type IV collagen. | journal=J Biol Chem | year= 1996 | volume= 271 | issue= 15 | pages= 9062-8 | pmid=8621555 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8621555 }} </ref><ref name="pmid2660143">{{cite journal| author=Jacob L, Viard JP, Allenet B, Anin MF, Slama FB, Vandekerckhove J et al.| title=A monoclonal anti-double-stranded DNA autoantibody binds to a 94-kDa cell-surface protein on various cell types via nucleosomes or a DNA-histone complex. | journal=Proc Natl Acad Sci U S A | year= 1989 | volume= 86 | issue= 12 | pages= 4669-73 | pmid=2660143 | doi= | pmc=PMC287332 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2660143 }} </ref> However, presence of [[antibodies]] alone is not sufficient for glomerular inflammation.<ref>{{cite book | last = Cibrik |first = DM | authorlink = | coauthors = Sedor JR | title = Immunopathogenesis of renal disease. In: Breenberg A, ed. Primer on kidney diseases. 2nd ed. | publisher = Academic Press |date = 1997 | location = San Diego, Calif | pages = 141-9 | url = | doi = | id = | isbn = }}</ref> Complexes formed by the antibody-antigen complexes must in fact be able to evade clearance by the [[reticuloendothelial system]] to effectively deposit at the [[glomerulus]].<ref name="pmid9744974">{{cite journal| author=Hricik DE, Chung-Park M, Sedor JR| title=Glomerulonephritis. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 13 | pages= 888-99 | pmid=9744974 | doi=10.1056/NEJM199809243391306 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9744974 }} </ref><ref>{{cite book | last = Wilson |first = CB | authorlink = | coauthors = | title = The renal response to immunologic injury. In: Brenner BM, Recror FC Jr, eds. The Kidney. 4th ed. | publisher = W.B. Saunders |date = 1991 | location = Philadelphia | pages = 1062-181 | url = | doi = | id = | isbn = }}</ref>
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| ===Role of Neutrophils===
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| When [[complement pathway]] is activated, complement-derived [[neutrophil]] chemotactic factors facilitate the infiltration of [[neutrophil]]s.<ref>{{cite book | last = Danoff |first = TM | authorlink = | coauthors = Nielson EG | title = The role of chemoattractants in renal disease (Chapter 24). In: Nielson EG, Couser WG, eds Immunologic renal diseases | publisher = Lippincott-Raven Publishers |date = 1997 | location = Philadelphia, PA | pages = 495-512 | url = | doi = | id = | isbn = }}</ref> [[Neutrophil]]s undergo respiratory burst to release toxic oxygen metabolites that are nephritogenic.<ref name="pmid3033023">{{cite journal| author=Johnson RJ, Couser WG, Chi EY, Adler S, Klebanoff SJ| title=New mechanism for glomerular injury. Myeloperoxidase-hydrogen peroxide-halide system. | journal=J Clin Invest | year= 1987 | volume= 79 | issue= 5 | pages= 1379-87 | pmid=3033023 | doi=10.1172/JCI112965 | pmc=PMC424393 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3033023 }} </ref><ref name="pmid2822992">{{cite journal| author=Johnson RJ, Klebanoff SJ, Ochi RF, Adler S, Baker P, Sparks L et al.| title=Participation of the myeloperoxidase-H2O2-halide system in immune complex nephritis. | journal=Kidney Int | year= 1987 | volume= 32 | issue= 3 | pages= 342-9 | pmid=2822992 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2822992 }} </ref> Hydrogen peroxide interacts with [[myeloperoxidase enzyme]] derived form the [[neutrophil]]s leading to a direct injury to the [[glomerular]] basement membrane.<ref name="pmid2822992">{{cite journal| author=Johnson RJ, Klebanoff SJ, Ochi RF, Adler S, Baker P, Sparks L et al.| title=Participation of the myeloperoxidase-H2O2-halide system in immune complex nephritis. | journal=Kidney Int | year= 1987 | volume= 32 | issue= 3 | pages= 342-9 | pmid=2822992 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2822992 }} </ref> Damage to the capillary wall and [[proteinuria]] have also been shown to be induced by [[elastase]] and cathepsin G, both of which are [[serine protease]]s derived from neutrophils.<ref>{{cite book | last = Johnson |first = RJ | authorlink = | coauthors = Klebanoff SJ, Couser WG | title = Neutrophils (Chapter 25). In: Nielson EG, Couser WG, eds Immunologic renal diseases | publisher = Lippincott-Raven Publishers |date = 1997 | location = Philadelphia, PA | pages = 512-541 | url = | doi = | id = | isbn = }}</ref><ref name="pmid2971672">{{cite journal| author=Johnson RJ, Alpers CE, Pritzl P, Schulze M, Baker P, Pruchno C et al.| title=Platelets mediate neutrophil-dependent immune complex nephritis in the rat. | journal=J Clin Invest | year= 1988 | volume= 82 | issue= 4 | pages= 1225-35 | pmid=2971672 | doi=10.1172/JCI113720 | pmc=PMC442673 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2971672 }} </ref>
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| ===Role of Platelets===
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| Platelets play a role in the neutrophil-mediated injury as well. It is believed that [[platelet]]s exacerbate the injury caused by [[neutrophil]]s in a mechanism that is yet to be understood.<ref name="pmid2971672">{{cite journal|author=Johnson RJ, Alpers CE, Pritzl P, Schulze M, Baker P, Pruchno C et al.| title=Platelets mediate neutrophil-dependent immune complex nephritis in the rat. | journal=J Clin Invest | year= 1988 |volume= 82 | issue= 4 | pages= 1225-35 | pmid=2971672 | doi=10.1172/JCI113720 | pmc=PMC442673 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2971672 }} </ref>
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| ===Role of Macrophages===
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| [[Macrophage]]s are involved in glomerular injury through the release of oxidants and [[protease]]s. These compounds help in the synthesis of tissue factor that leads to deposition of fibrin material on the [[glomerulus]]. Subsequently, [[cytokine]]s and [[growth factor]]s, such as [[IL-1]] and TGF-B, are released and cause the abnormal production of [[extracellular matrix]].<ref>{{cite book | last = Nikolick-Patterson |first = DJ | authorlink = |coauthors = Lan HY, Atkins RC | title = Macrophages (Chapter 28). In: Nielson EG, Couser WG, eds Immunologic renal diseases | publisher = Lippincott-Raven Publishers |date = 1997 | location = Philadelphia, PA | pages = 567-586 | url = | doi = | id = | isbn = }}</ref><ref>{{cite book | last = Floege |first = J | authorlink = |coauthors = Rees, AJ | title = Growth factors and cytokines (Chapter 20). In: Nielson EG, Couser WG, eds Immunologic renal diseases | publisher = Lippincott-Raven Publishers |date = 1997 | location = Philadelphia, PA | pages = 415-452| url = | doi = | id = | isbn = }}</ref>
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| ===Role of T Cells===
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| T cells are important for inducing glomerular hypercellularity.<ref name="pmid315992">{{cite journal| author=Bhan AK, Collins AB, Schneeberger EE, McCluskey RT| title=A cell-mediated reaction against glomerular-bound immune complexes. | journal=J Exp Med | year= 1979 | volume= 150 | issue= 6 | pages= 1410-20 | pmid=315992 | doi= | pmc=PMC2185734 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=315992 }} </ref> T cells are present in both proliferative and non-proliferative glomerular diseases.<ref name="pmid7552103">{{cite journal| author=Main IW, Atkins RC| title=The role of T-cells in inflammatory kidney disease. | journal=Curr Opin Nephrol Hypertens | year= 1995 | volume= 4 | issue= 4 | pages= 354-8 | pmid=7552103 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7552103 }} </ref> Pro-inflammatory pathways are activated following initial injury to induce further synthesis of [[cytokine]]s, [[complement activation]], influx of circulating [[leukocyte]]s, release of proteolytic enzymes, and activation of coagulation pathway.<ref name="pmid8361123">{{cite journal| author=Couser WG| title=Pathogenesis of glomerulonephritis. | journal=Kidney Int Suppl | year= 1993 | volume= 42 | issue= | pages= S19-26 | pmid=8361123 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8361123 }} </ref><ref name="pmid7933825">{{cite journal| author=Johnson RJ| title=The glomerular response to injury: progression or resolution? | journal=Kidney Int | year= 1994 | volume= 45 | issue= 6 | pages= 1769-82 | pmid=7933825 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7933825 }} </ref> These changes make the glomerular cell itself, in addition to the infiltrating glomerular cells, an active component of destruction and subsequent restoration.<ref name="pmid7933825">{{cite journal| author=Johnson RJ| title=The glomerular response to injury: progression or resolution? | journal=Kidney Int | year= 1994 | volume= 45 | issue= 6 | pages= 1769-82 | pmid=7933825 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7933825 }} </ref><ref name="pmid8468928">{{cite journal| author=Sedor JR, Konieczkowski M, Huang S, Gronich JH, Nakazato Y, Gordon G et al.| title=Cytokines, mesangial cell activation and glomerular injury. | journal=Kidney Int Suppl | year= 1993 | volume= 39 | issue= | pages= S65-70 | pmid=8468928 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8468928 }} </ref><ref name="pmid9358740">{{cite journal| author=Johnson RJ| title=What mediates progressive glomerulosclerosis? The glomerular endothelium comes of age. | journal=Am J Pathol | year= 1997 | volume= 151 | issue= 5 | pages= 1179-81 | pmid=9358740 | doi= | pmc=PMC1858081 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9358740 }} </ref>
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| ===Matrix Remodeling===
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| Matrix remodeling is in part involved in the activation and proliferation of glomerular cells. The resident and the infiltrating cells will both receive unique signals following matrix remodeling that are involved in the activation of pro-inflammatory pathways in these cells.<ref name="pmid9744974">{{cite journal| author=Hricik DE, Chung-Park M, Sedor JR| title=Glomerulonephritis. | journal=N Engl J Med | year= 1998 | volume= 339 | issue= 13 | pages= 888-99 | pmid=9744974 | doi=10.1056/NEJM199809243391306 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9744974 }} </ref> [[Autocrine]] activation of platelet-derived growth factors (PDGF) B-chain and ''B''-receptors is believed to cause the proliferation of mesangial cells during glomerular injury.<ref name="pmid1569407">{{cite journal| author=Johnson RJ, Raines EW, Floege J, Yoshimura A, Pritzl P, Alpers C et al.| title=Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. | journal=J Exp Med | year= 1992 | volume= 175 | issue= 5 | pages= 1413-6 | pmid=1569407 | doi= | pmc=PMC2119215 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1569407 }} </ref> Growth factors ultimately cause the increase in [[proteinase]] synthesis and matrix expansion.<ref name="pmid1321565">{{cite journal| author=Lovett DH, Johnson RJ, Marti HP, Martin J, Davies M, Couser WG| title=Structural characterization of the mesangial cell type IV collagenase and enhanced expression in a model of immune complex-mediated glomerulonephritis. | journal=Am J Pathol | year= 1992 | volume= 141 | issue= 1 | pages= 85-98 | pmid=1321565 | doi= | pmc=PMC1886574 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1321565 }} </ref><ref name="pmid7935686">{{cite journal| author=Border WA, Noble NA| title=Transforming growth factor beta in tissue fibrosis. | journal=N Engl J Med | year= 1994 | volume= 331 | issue= 19 | pages= 1286-92 | pmid=7935686 | doi=10.1056/NEJM199411103311907 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7935686 }} </ref>
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| ===Adaptive Mechanisms===
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| Due to ongoing injury, adaptive changes take place in order to help in the resolution of [[glomerulonephritis]]. Hyperfiltration, intraglomerular hypertension, and irregular intravascular stress and shear are all processes that may on one hand worsen the [[renal injury]], but are also crucial for the remainder of the functioning glomerulus.<ref name="pmid7933825">{{cite journal| author=Johnson RJ| title=The glomerular response to injury: progression or resolution? | journal=Kidney Int | year= 1994 | volume= 45 | issue= 6 | pages= 1769-82 | pmid=7933825 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7933825 }} </ref><ref name="pmid8468928">{{cite journal| author=Sedor JR, Konieczkowski M, Huang S, Gronich JH, Nakazato Y, Gordon G et al.| title=Cytokines, mesangial cell activation and glomerular injury. | journal=Kidney Int Suppl | year= 1993 | volume= 39 | issue= | pages= S65-70 | pmid=8468928 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8468928 }} </ref><ref name="pmid9358740">{{cite journal| author=Johnson RJ| title=What mediates progressive glomerulosclerosis? The glomerular endothelium comes of age. | journal=Am J Pathol | year= 1997 | volume= 151 | issue= 5 | pages= 1179-81 | pmid=9358740 | doi= | pmc=PMC1858081 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9358740 }} </ref><ref name="pmid8743495">{{cite journal| author=Brenner BM, Lawler EV, Mackenzie HS| title=The hyperfiltration theory: a paradigm shift in nephrology. | journal=Kidney Int | year= 1996 | volume= 49 | issue= 6 | pages= 1774-7 | pmid=8743495 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8743495 }} </ref>
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| ===Resolution of Disease===
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| [[Apoptosis]], defined as programmed cell death, plays a significant role in defining the resolution of disease and in the renal scarring following [[glomerulonephritis]].<ref name="pmid8731187">{{cite journal| author=Savill J, Mooney A, Hughes J| title=Apoptosis and renal scarring. | journal=Kidney Int Suppl | year= 1996 | volume= 54 | issue= | pages= S14-7 | pmid=8731187 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8731187 }} </ref>
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| ==References==
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| {{reflist|2}}
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| {{WH}}
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| {{WS}}
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| [[Category:Needs content]]
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| [[Category:Disease]]
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| [[Category:Nephrology]]
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| [[Category:Syndromes]]
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| [[Category:Pediatrics]]
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