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{{Rapidly progressive glomerulonephritis}} | {{Rapidly progressive glomerulonephritis}} | ||
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==Overview== | |||
==Pathophysiology== | |||
==[[Rapidly progressive glomerulonephritis pathophysiology|Pathophysiology]]== | |||
The pathogenesis of RPGN is unclear and is poorly understood. Nonetheless, circulating factors are thought to play a significant role in the disease and its progression.<ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref> RPGN, as an outcome, seems to be actually related to the type of RPGN. As such, there does not seem to be a unifying pathophysiology, but rather a combination of pathways that lead to a similar renal outcome. Genetic susceptibility has been shown to be associated with elevated levels of circulating antibodies, such as anti-GBM and ANCA, but little has been elaborated.<ref name="pmid7544065">{{cite journal| author=Short AK, Esnault VL, Lockwood CM| title=Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis. | journal=Am J Kidney Dis | year= 1995 | volume= 26 | issue= 3 | pages= 439-45 | pmid=7544065 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7544065 }} </ref> | |||
In type I anti-GBM glomerulonephritis, antibodies against the non-collagenous domain of alpha-3 chain of type IV collagen of the glomerular basement membrane with a linear pattern on immunofluorescence are responsible for renal involvement.<ref name="pmid18590526">{{cite journal| author=Ramaswami A, Kandaswamy T, Rajendran T, Aung H, Jacob CK, Zinna HS et al.| title=Goodpasture's syndrome with positive C-ANCA and normal renal function: a case report. | journal=J Med Case Rep | year= 2008 | volume= 2 | issue= | pages= 223 | pmid=18590526 | doi=10.1186/1752-1947-2-223 | pmc=PMC2475522 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18590526 }} </ref><ref name="pmid4937848">{{cite journal| author=Lewis EJ, Cavallo T, Harrington JT, Cotran RS| title=An immunopathologic study of rapidly progressive glomerulonephritis in the adult. | journal=Hum Pathol | year= 1971 | volume= 2 | issue= 2 | pages= 185-208 | pmid=4937848 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4937848 }} </ref><ref name="pmid7360526">{{cite journal| author=Cunningham RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M et al.| title=Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature. | journal=Pediatr Res | year= 1980 | volume= 14 | issue= 2 | pages= 128-32 | pmid=7360526 | doi=10.1203/00006450-198002000-00012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7360526 }} </ref> The granular distribution along the GBM exhibit IgG and C3 deposits. Crescent formation is predominantly due to the formation of fibrin/fibrinogen.<ref name="pmid7360526">{{cite journal| author=Cunningham RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M et al.| title=Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature. | journal=Pediatr Res | year= 1980 | volume= 14 | issue= 2 | pages= 128-32 | pmid=7360526 | doi=10.1203/00006450-198002000-00012 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7360526 }} </ref> | |||
In Type II pauci-immune glomerulonephritis, such as in polyangiitis with granulomatosis (formerly Wegener granulomatosis) and polyarteritis nodosa, findings of p-ANCA and c-ANCA in patients are considered landmarks in understanding these diseases; but their true significance has not yet been delineated.<ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref><ref name="pmid6297657">{{cite journal| author=Davies DJ, Moran JE, Niall JF, Ryan GB| title=Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? | journal=Br Med J (Clin Res Ed) | year= 1982 | volume= 285 | issue= 6342 | pages= 606 | pmid=6297657 | doi= | pmc=PMC1499415 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6297657 }} </ref> Studies have shown that ANCA may in fact interact with neutrophils due to the presence of myeloperixoidases on the surface of neutrophils. The interaction drives neutrophils to undergo activation via oxidative burst that finally leads to their “dose-dependent” degranulation and release of toxic oxygen radicals.<ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref> TNF priming also seems to play an important role in the ANCA-induced degranulation of neutrophils.<ref name="pmid3009619">{{cite journal| author=Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM et al.| title=Stimulation of neutrophils by tumor necrosis factor. | journal=J Immunol | year= 1986 | volume= 136 | issue= 11 | pages= 4220-5 | pmid=3009619 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3009619 }} </ref><ref name="pmid7044447">{{cite journal| author=Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N| title=Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. | journal=Blood | year= 1982 | volume= 59 | issue= 6 | pages= 1317-29 | pmid=7044447 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7044447 }} </ref> As such, it is perhaps that TNF production during infections and inflammatory diseases in vivo may prime neutrophils in ANCA-positive patients to facilitate neutrophilic activation and subsequent pro-inflammatory cascade of RPGN disease.<ref name="pmid2161532">{{cite journal| author=Falk RJ, Terrell RS, Charles LA, Jennette JC| title=Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. | journal=Proc Natl Acad Sci U S A | year= 1990 | volume= 87 | issue= 11 | pages= 4115-9 | pmid=2161532 | doi= | pmc=PMC54058 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2161532 }} </ref><ref name="pmid3009619">{{cite journal| author=Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM et al.| title=Stimulation of neutrophils by tumor necrosis factor. | journal=J Immunol | year= 1986 | volume= 136 | issue= 11 | pages= 4220-5 | pmid=3009619 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3009619 }} </ref><ref name="pmid7044447">{{cite journal| author=Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N| title=Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. | journal=Blood | year= 1982 | volume= 59 | issue= 6 | pages= 1317-29 | pmid=7044447 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7044447 }} </ref> | |||
While the majority of patients with pauci-immune RPGN indeed have elevated levels of ANCA, the remaining 20% of patients with the same disease do not. Interestingly, 30% of patients in remission continue to have elevated levels of ANCA. Both these problematic findings raise the question of the actual importance of ANCA in the pathogenesis of RPGN.<ref name="pmid11007827">{{cite journal| author=Hedger N, Stevens J, Drey N, Walker S, Roderick P| title=Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study. | journal=Nephrol Dial Transplant | year= 2000 | volume= 15 | issue= 10 | pages= 1593-9 | pmid=11007827 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11007827 }} </ref> A novel hypothesis currently suggests that RPGN is in fact a podocytopathy, defined as an intrinsic disease of the podocytes that normally maintains glomerular capillary membranes.<ref name="pmid14675045">{{cite journal| author=Yoshimoto K, Yokoyama H, Wada T, Furuichi K, Sakai N, Iwata Y et al.| title=Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy. | journal=Kidney Int | year= 2004 | volume= 65 | issue= 1 | pages= 148-53 | pmid=14675045 | doi=10.1111/j.1523-1755.2004.00403.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14675045 }} </ref> As such, it is thought that the CXCR4 and VHL-HIF pathway target gene expression in renal biopsies, based on experimental studies on mice.<ref name="pmid16906157">{{cite journal| author=Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM et al.| title=Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice. | journal=Nat Med | year= 2006 | volume= 12 | issue= 9 | pages= 1081-7 | pmid=16906157 | doi=10.1038/nm1460 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16906157 }} </ref> | |||
==References== | ==References== | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
Pathophysiology
The pathogenesis of RPGN is unclear and is poorly understood. Nonetheless, circulating factors are thought to play a significant role in the disease and its progression.[1] RPGN, as an outcome, seems to be actually related to the type of RPGN. As such, there does not seem to be a unifying pathophysiology, but rather a combination of pathways that lead to a similar renal outcome. Genetic susceptibility has been shown to be associated with elevated levels of circulating antibodies, such as anti-GBM and ANCA, but little has been elaborated.[2]
In type I anti-GBM glomerulonephritis, antibodies against the non-collagenous domain of alpha-3 chain of type IV collagen of the glomerular basement membrane with a linear pattern on immunofluorescence are responsible for renal involvement.[3][4][5] The granular distribution along the GBM exhibit IgG and C3 deposits. Crescent formation is predominantly due to the formation of fibrin/fibrinogen.[5]
In Type II pauci-immune glomerulonephritis, such as in polyangiitis with granulomatosis (formerly Wegener granulomatosis) and polyarteritis nodosa, findings of p-ANCA and c-ANCA in patients are considered landmarks in understanding these diseases; but their true significance has not yet been delineated.[1][6] Studies have shown that ANCA may in fact interact with neutrophils due to the presence of myeloperixoidases on the surface of neutrophils. The interaction drives neutrophils to undergo activation via oxidative burst that finally leads to their “dose-dependent” degranulation and release of toxic oxygen radicals.[1] TNF priming also seems to play an important role in the ANCA-induced degranulation of neutrophils.[7][8] As such, it is perhaps that TNF production during infections and inflammatory diseases in vivo may prime neutrophils in ANCA-positive patients to facilitate neutrophilic activation and subsequent pro-inflammatory cascade of RPGN disease.[1][7][8]
While the majority of patients with pauci-immune RPGN indeed have elevated levels of ANCA, the remaining 20% of patients with the same disease do not. Interestingly, 30% of patients in remission continue to have elevated levels of ANCA. Both these problematic findings raise the question of the actual importance of ANCA in the pathogenesis of RPGN.[9] A novel hypothesis currently suggests that RPGN is in fact a podocytopathy, defined as an intrinsic disease of the podocytes that normally maintains glomerular capillary membranes.[10] As such, it is thought that the CXCR4 and VHL-HIF pathway target gene expression in renal biopsies, based on experimental studies on mice.[11]
References
- ↑ 1.0 1.1 1.2 1.3 Falk RJ, Terrell RS, Charles LA, Jennette JC (1990). "Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro". Proc Natl Acad Sci U S A. 87 (11): 4115–9. PMC 54058. PMID 2161532.
- ↑ Short AK, Esnault VL, Lockwood CM (1995). "Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis". Am J Kidney Dis. 26 (3): 439–45. PMID 7544065.
- ↑ Ramaswami A, Kandaswamy T, Rajendran T, Aung H, Jacob CK, Zinna HS; et al. (2008). "Goodpasture's syndrome with positive C-ANCA and normal renal function: a case report". J Med Case Rep. 2: 223. doi:10.1186/1752-1947-2-223. PMC 2475522. PMID 18590526.
- ↑ Lewis EJ, Cavallo T, Harrington JT, Cotran RS (1971). "An immunopathologic study of rapidly progressive glomerulonephritis in the adult". Hum Pathol. 2 (2): 185–208. PMID 4937848.
- ↑ 5.0 5.1 Cunningham RJ, Gilfoil M, Cavallo T, Brouhard BH, Travis LB, Berger M; et al. (1980). "Rapidly progressive glomerulonephritis in children: a report of thirteen cases and a review of the literature". Pediatr Res. 14 (2): 128–32. doi:10.1203/00006450-198002000-00012. PMID 7360526.
- ↑ Davies DJ, Moran JE, Niall JF, Ryan GB (1982). "Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology?". Br Med J (Clin Res Ed). 285 (6342): 606. PMC 1499415. PMID 6297657.
- ↑ 7.0 7.1 Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM; et al. (1986). "Stimulation of neutrophils by tumor necrosis factor". J Immunol. 136 (11): 4220–5. PMID 3009619.
- ↑ 8.0 8.1 Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N (1982). "Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response". Blood. 59 (6): 1317–29. PMID 7044447.
- ↑ Hedger N, Stevens J, Drey N, Walker S, Roderick P (2000). "Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10-year retrospective study". Nephrol Dial Transplant. 15 (10): 1593–9. PMID 11007827.
- ↑ Yoshimoto K, Yokoyama H, Wada T, Furuichi K, Sakai N, Iwata Y; et al. (2004). "Pathologic findings of initial biopsies reflect the outcomes of membranous nephropathy". Kidney Int. 65 (1): 148–53. doi:10.1111/j.1523-1755.2004.00403.x. PMID 14675045.
- ↑ Ding M, Cui S, Li C, Jothy S, Haase V, Steer BM; et al. (2006). "Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice". Nat Med. 12 (9): 1081–7. doi:10.1038/nm1460. PMID 16906157.