Membranous glomerulonephritis: Difference between revisions
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'''Membranous glomerulonephritis ''' ('''MGN''') is a slowly progressive disease of the [[kidney]] affecting mostly people between ages of 30 and 50 years, usually Caucasian. |
'''Membranous glomerulonephritis ''' ('''MGN''') is a slowly progressive disease of the [[kidney]] affecting mostly people between ages of 30 and 50 years, usually Caucasian. |
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It is the second most common cause of [[nephrotic syndrome]] in adults, with [[focal segmental glomerulosclerosis]] (FSGS) recently becoming the most common.<ref>{{ |
It is the second most common cause of [[nephrotic syndrome]] in adults, with [[focal segmental glomerulosclerosis]] (FSGS) recently becoming the most common.<ref>{{EMedicine|article|239799|Membranous Glomerulonephritis}}</ref> |
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==Signs and symptoms== |
==Signs and symptoms== |
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===Primary/idiopathic=== |
===Primary/idiopathic=== |
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85% of MGN cases are classified as ''primary membranous glomerulonephritis''—that is to say, the cause of the disease is [[idiopathic]] (of unknown origin or cause). This can also be referred to as ''idiopathic membranous nephropathy''. One study has identified antibodies to an M-type [[phospholipase A]]<sub>2</sub> receptor in 70% (26 of 37) cases evaluated.<ref>{{cite journal |
85% of MGN cases are classified as ''primary membranous glomerulonephritis''—that is to say, the cause of the disease is [[idiopathic]] (of unknown origin or cause). This can also be referred to as ''idiopathic membranous nephropathy''. One study has identified antibodies to an M-type [[phospholipase A]]<sub>2</sub> receptor in 70% (26 of 37) cases evaluated.<ref>{{cite journal |doi=10.1056/NEJMoa0810457 }}</ref> In 2014, a second autoantigen was discovered, the thrombospondin type 1 domain-containing 7A (THSD7A) system that might account for an additional 5-10% of membranous nephropathy cases.<ref>{{cite journal |pmid=25394321 }}</ref> Other studies have implicated [[neutral endopeptidase]] and cationic bovine serum [[albumin]] as antigens.<ref name=Ronco2012>{{cite journal |doi=10.1038/nrneph.2012.35 }}</ref> |
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of membranous nephropathy cases |
of membranous nephropathy cases |
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* '''[[drug]]s''' (e.g., [[captopril]], [[NSAIDs]], [[penicillamine]], [[probenecid]]). |
* '''[[drug]]s''' (e.g., [[captopril]], [[NSAIDs]], [[penicillamine]], [[probenecid]]). |
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* '''inorganic [[salt]]s''' (e.g. [[gold]], [[mercury (element)|mercury]]). |
* '''inorganic [[salt]]s''' (e.g. [[gold]], [[mercury (element)|mercury]]). |
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* '''[[tumor]]s''', frequently solid tumors of the [[lung cancer|lung]] and [[colon cancer|colon]]; hematological malignancies such as [[chronic lymphocytic leukemia]] are less common.<ref name="pmid15224365">{{cite journal |
* '''[[tumor]]s''', frequently solid tumors of the [[lung cancer|lung]] and [[colon cancer|colon]]; hematological malignancies such as [[chronic lymphocytic leukemia]] are less common.<ref name="pmid15224365">{{cite journal |doi=10.1002/ajh.20109 }}</ref> |
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==Pathogenesis== |
==Pathogenesis== |
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The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a [[Complement membrane attack complex|membrane attack complex]] (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces [[nephrin]] synthesis and distribution. |
The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a [[Complement membrane attack complex|membrane attack complex]] (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces [[nephrin]] synthesis and distribution. |
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Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low.<ref name="Menon2009">{{cite journal |
Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low.<ref name="Menon2009">{{cite journal |doi=10.1007/s00467-009-1324-5 }}</ref> |
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Similar to other causes of nephrotic syndrome (e.g., [[focal segmental glomerulosclerosis]] or [[minimal change disease]]), membranous nephropathy is known to predispose affected individuals to develop [[thrombosis|blood clots]] such as [[pulmonary embolism|pulmonary emboli]]. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear. |
Similar to other causes of nephrotic syndrome (e.g., [[focal segmental glomerulosclerosis]] or [[minimal change disease]]), membranous nephropathy is known to predispose affected individuals to develop [[thrombosis|blood clots]] such as [[pulmonary embolism|pulmonary emboli]]. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear. |
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* [[Immunoflourescence|Immunofluorescence]] microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.<ref name="urlRenal Pathology">{{cite web |url=http://library.med.utah.edu/WebPath/RENAHTML/RENAL090.html |title=Renal Pathology |work= |accessdate=2008-11-25}}</ref> |
* [[Immunoflourescence|Immunofluorescence]] microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.<ref name="urlRenal Pathology">{{cite web |url=http://library.med.utah.edu/WebPath/RENAHTML/RENAL090.html |title=Renal Pathology |work= |accessdate=2008-11-25}}</ref> |
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Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.<ref name="pmid17699279">{{cite journal |
Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.<ref name="pmid17699279">{{cite journal |doi=10.2215/CJN.01211005 }}</ref> |
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==Treatment== |
==Treatment== |
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Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy, the treatment options include [[immunosuppressive]] drugs and non-specific anti-proteinuric measures. Recommended first line therapy often includes: [[cyclophosphamide]] alternating with a [[corticosteroid]].<ref>{{cite journal |
Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy, the treatment options include [[immunosuppressive]] drugs and non-specific anti-proteinuric measures. Recommended first line therapy often includes: [[cyclophosphamide]] alternating with a [[corticosteroid]].<ref name=pmid25318831>{{cite journal |doi=10.1002/14651858.CD004293.pub3 }}</ref> |
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===Immunosuppressive therapy=== |
===Immunosuppressive therapy=== |
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# [[Corticosteroids]]: They have been tried with mixed results, with one study showing prevention of progression to [[kidney failure]] without improvement in [[proteinuria]]. |
# [[Corticosteroids]]: They have been tried with mixed results, with one study showing prevention of progression to [[kidney failure]] without improvement in [[proteinuria]]. |
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# [[Chlorambucil]] |
# [[Chlorambucil]] |
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# [[Cyclosporine]]<ref name="pmid17389782">{{cite journal |doi=10.1159/000101367 }}</ref> |
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# [[Cyclosporine]]<ref name="pmid17389782">{{cite journal |vauthors=Goumenos DS, Katopodis KP, Passadakis P, etal |title=Corticosteroids and ciclosporin A in idiopathic membranous nephropathy: higher remission rates of nephrotic syndrome and less adverse reactions than after traditional treatment with cytotoxic drugs |journal=Am. J. Nephrol. |volume=27 |issue=3 |pages=226–31 |year=2007 |pmid=17389782 |doi=10.1159/000101367 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000101367}}</ref> |
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# [[Tacrolimus]] |
# [[Tacrolimus]] |
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# [[Cyclophosphamide]] |
# [[Cyclophosphamide]] |
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==Terminology== |
==Terminology== |
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The closely related terms membranous [[nephropathy]]<ref name="pmid12923723">{{cite journal |
The closely related terms membranous [[nephropathy]]<ref name="pmid12923723">{{cite journal |doi=10.1016/S0270-9295(03)00052-4 }}</ref> and membranous [[glomerulopathy]]<ref name="pmid11345236">{{cite journal |doi=10.1097/00125480-200105000-00001 }}</ref> both refer to a similar constellation but without the assumption of [[inflammation]]. |
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Membranous [[nephritis]] (in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered.<ref name="pmid10866094">{{cite journal |
Membranous [[nephritis]] (in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered.<ref name="pmid10866094">{{cite journal |doi=10.1191/096120300680198935 }}</ref> These conditions are usually considered together. |
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By contrast, [[membranoproliferative glomerulonephritis]] has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative [[glomerulonephritis]] involves the [[basement membrane]] and [[mesangium]], while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.) |
By contrast, [[membranoproliferative glomerulonephritis]] has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative [[glomerulonephritis]] involves the [[basement membrane]] and [[mesangium]], while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.) |
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Revision as of 22:15, 19 August 2018
| Membranous glomerulonephritis | |
|---|---|
 | |
| Micrograph of membranous nephropathy showing prominent glomerular basement membrane spikes. Jones' stain. | |
| Specialty | Nephrology  |
Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually Caucasian.
It is the second most common cause of nephrotic syndrome in adults, with focal segmental glomerulosclerosis (FSGS) recently becoming the most common.[1]
Signs and symptoms
Some people may present as nephrotic syndrome with proteinuria, edema with or without kidney failure. Others may not have symptoms and may be picked up on screening or urinalysis as having high amounts of protein loss in the urine. A definitive diagnosis of membranous nephropathy requires a kidney biopsy.
Causes
Primary/idiopathic
85% of MGN cases are classified as primary membranous glomerulonephritis—that is to say, the cause of the disease is idiopathic (of unknown origin or cause). This can also be referred to as idiopathic membranous nephropathy. One study has identified antibodies to an M-type phospholipase A2 receptor in 70% (26 of 37) cases evaluated.[2] In 2014, a second autoantigen was discovered, the thrombospondin type 1 domain-containing 7A (THSD7A) system that might account for an additional 5-10% of membranous nephropathy cases.[3] Other studies have implicated neutral endopeptidase and cationic bovine serum albumin as antigens.[4]
of membranous nephropathy cases
Secondary
The remainder is secondary due to:
- autoimmune conditions (e.g., systemic lupus erythematosus[5])
- infections (e.g., syphilis, malaria, hepatitis B, hepatitis C)
- drugs (e.g., captopril, NSAIDs, penicillamine, probenecid).
- inorganic salts (e.g. gold, mercury).
- tumors, frequently solid tumors of the lung and colon; hematological malignancies such as chronic lymphocytic leukemia are less common.[6]
Pathogenesis
MGN is caused by immune complex formation in the glomerulus. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane. The antigens may be part of the basement membrane, or deposited from elsewhere by the systemic circulation.
The immune complex serves as an activator that triggers a response from the C5b - C9 complements, which form a membrane attack complex (MAC) on the glomerular epithelial cells. This, in turn, stimulates release of proteases and oxidants by the mesangial and epithelial cells, damaging the capillary walls and causing them to become "leaky". In addition, the epithelial cells also seem to secrete an unknown mediator that reduces nephrin synthesis and distribution.
Within membranous glomerulonephritis, especially in cases caused by viral hepatitis, serum C3 levels are low.[7]
Similar to other causes of nephrotic syndrome (e.g., focal segmental glomerulosclerosis or minimal change disease), membranous nephropathy is known to predispose affected individuals to develop blood clots such as pulmonary emboli. Membranous nephropathy in particular is known to increase this risk more than other causes of nephrotic syndrome though the reason for this is not yet clear.
Morphology
The defining point of MGN is the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membrane (GBM).
- By light microscopy, the basement membrane is observed to be diffusely thickened. Using Jones' stain, the GBM appears to have a "spiked" or "holey" appearance.
- On electron microscopy, subepithelial deposits that nestle against the glomerular basement membrane seems to be the cause of the thickening. Also, the podocytes lose their foot processes. As the disease progresses, the deposits will eventually be cleared, leaving cavities in the basement membrane. These cavities will later be filled with basement membrane-like material, and if the disease continues even further, the glomeruli will become sclerosed and finally hyalinized.
- Immunofluorescence microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.[8]
Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.[9]
Treatment
Treatment of secondary membranous nephropathy is guided by the treatment of the original disease. For treatment of idiopathic membranous nephropathy, the treatment options include immunosuppressive drugs and non-specific anti-proteinuric measures. Recommended first line therapy often includes: cyclophosphamide alternating with a corticosteroid.[10]
Immunosuppressive therapy
- Corticosteroids: They have been tried with mixed results, with one study showing prevention of progression to kidney failure without improvement in proteinuria.
- Chlorambucil
- Cyclosporine[11]
- Tacrolimus
- Cyclophosphamide
- Mycophenolate mofetil
- Rituximab
Perhaps the most difficult aspect of membranous glomerulonephritis is deciding which people to treat with immunosuppressive therapy as opposed to simple "background" or anti-proteinuric therapies. A large part of this difficulty is due to a lack of ability to predict which people will progress to end-stage kidney disease, or kidney disease severe enough to require dialysis. Because the above medications carry risk, treatment should not be initiated without careful consideration as to risk/benefit profile. Of note, corticosteroids (typically Prednisone) alone are of little benefit. They should be combined with one of the other 5 medications, each of which, along with prednisone, has shown some benefit in slowing down progression of membranous nephropathy. It must be kept in mind, however, that each of the 5 medications also carry their own risks, on top of prednisone.
The twin aims of treating membranous nephropathy are first to induce a remission of the nephrotic syndrome and second to prevent the development of end-stage kidney failure. A meta-analysis of four randomized controlled trials comparing treatments of membranous nephropathy showed that regimes comprising chlorambucil or cyclophosphamide, either alone or with steroids, were more effective than symptomatic treatment or treatment with steroids alone in inducing remission of the nephrotic syndrome.
Prognosis
About a third of untreated patients have spontaneous remission, another third progress to require dialysis and the last third continue to have proteinuria, without progression of kidney failure.
Terminology
The closely related terms membranous nephropathy[12] and membranous glomerulopathy[13] both refer to a similar constellation but without the assumption of inflammation.
Membranous nephritis (in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered.[14] These conditions are usually considered together.
By contrast, membranoproliferative glomerulonephritis has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative glomerulonephritis involves the basement membrane and mesangium, while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.)
References
- ^ Membranous Glomerulonephritis at eMedicine
- ^ . doi:10.1056/NEJMoa0810457.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . PMID 25394321.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1038/nrneph.2012.35.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ "Renal Pathology". Retrieved 2008-11-25.
- ^ . doi:10.1002/ajh.20109.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1007/s00467-009-1324-5.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ "Renal Pathology". Retrieved 2008-11-25.
- ^ . doi:10.2215/CJN.01211005.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1002/14651858.CD004293.pub3.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1159/000101367.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1016/S0270-9295(03)00052-4.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1097/00125480-200105000-00001.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1191/096120300680198935.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help)