Membranous glomerulonephritis
Encyclopedia
Membranous glomerulonephritis
(MGN) is a slowly progressive disease of the kidney
affecting mostly patients between ages of 30 and 50 years, usually Caucasian.
It is one of the more common forms of nephrotic syndrome.
and membranous glomerulopathy
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. 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.)
(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.
. 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.
(GBM).
Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.
with proteinuria
, edema
with or without renal failure
. Others may be asymptomatic and may be picked up on screening or urinalysis
as having proteinuria
. A definitive diagnosis of membranous nephropathy requires a kidney biopsy
.
Perhaps the most difficult aspect of membranous glomerulonpehritis is deciding which patients 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 patient will progress to end-stage renal disease, or renal 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 endstage renal failure. A meta-analysis of four randomized controlled studies 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. A small, randomized controlled study of 17 patients with a persistent nephrotic syndrome and declining renal function suggested that ciclosporin A slowed the rate of decline of renal function: this requires confirmation in a larger trial.
and the last third continue to have proteinuria, without progression of renal failure
.
Glomerulonephritis
Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by inflammation of the glomeruli, or small blood vessels in the kidneys...
(MGN) is a slowly progressive disease of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
affecting mostly patients between ages of 30 and 50 years, usually Caucasian.
It is one of the more common forms of nephrotic syndrome.
Terminology
-The closely related terms membranous nephropathyNephropathy
Nephropathy refers to damage to or disease of the kidney. An older term for this is nephrosis.-Causes:Causes of nephropathy include administration of analgesics, xanthine oxidase deficiency, and long-term exposure to lead or its salts...
and membranous glomerulopathy
Glomerulopathy
Glomerulopathy is a term used to describe a disease affecting the glomeruli of the nephron.It can refer to a process that is inflammatory or noninflammatory. Because the term "glomerulitis" exists for inflammatory conditions, "glomerulopathy" sometimes carries a noninflammatory implication....
both refer to a similar constellation but without the assumption of inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
.
-Membranous nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....
(in which inflammation is implied, but the glomerulus not explicitly mentioned) is less common, but the phrase is occasionally encountered. These conditions are usually considered together.
By contrast, membranoproliferative glomerulonephritis
Membranoproliferative glomerulonephritis
Membranoproliferative glomerulonephritis , also known as mesangiocapillary glomerulonephritis, is a type of glomerulonephritis caused by deposits in the kidney glomerular mesangium and basement membrane thickening, activating complement and damaging the glomeruli.MPGN accounts for approximately 4%...
has a similar name, but is considered a separate condition with a distinctly different causality. Membranoproliferative glomerulonephritis involves the basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
and mesangium
Mesangium
The mesangium is an inner layer of the glomerulus, within the basement membrane surrounding the glomerular capillaries. This term is often used interchangeably with mesangial cell, but in this context refers specifically to the intraglomerular mesangial cells. These cells are phagocytic and secrete...
, while membranous glomerulonephritis involves the basement membrane but not the mesangium. (Membranoproliferative glomerulonephritis has the alternate name "mesangiocapillary glomerulonephritis", to emphasize its mesangial character.)
Primary/idiopathic
85% of MGN cases are classified as primary membranous glomerulonephritis -- that is to say, the cause of the disease is idiopathicIdiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
(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.
Secondary
The remainder is secondary due to:- autoimmune conditions (e.g., systemic lupus erythematosusSystemic lupus erythematosusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
) - infectionInfectionAn infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s (e.g., syphilisSyphilisSyphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
, malariaMalariaMalaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
, hepatitis B) - drugDrugA drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...
s (e.g., captoprilCaptoprilCaptopril is an angiotensin-converting enzyme inhibitor used for the treatment of hypertension and some types of congestive heart failure. Captopril was the first ACE inhibitor developed and was considered a breakthrough both because of its novel mechanism of action and also because of the...
, NSAIDs, goldGoldGold is a chemical element with the symbol Au and an atomic number of 79. Gold is a dense, soft, shiny, malleable and ductile metal. Pure gold has a bright yellow color and luster traditionally considered attractive, which it maintains without oxidizing in air or water. Chemically, gold is a...
, mercuryMercury (element)Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
, penicillaminePenicillaminePenicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...
, probenecidProbenecidProbenecid is a uricosuric drug that increases uric acid excretion in the urine. It is primarily used in treating gout and hyperuricemia.Probenecid was developed as an alternative to caronamide...
). - inorganic saltSaltIn chemistry, salts are ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of cations and anions so that the product is electrically neutral...
s - tumorTumorA tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
s, frequently solid tumors of the lungLung cancerLung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
and colon; hematological malignancies such as chronic lymphocytic leukemiaChronic lymphocytic leukemiaB-cell chronic lymphocytic leukemia , also known as chronic lymphoid leukemia , is the most common type of leukemia. Leukemias are cancers of the white blood cells . CLL affects B cell lymphocytes. B cells originate in the bone marrow, develop in the lymph nodes, and normally fight infection by...
are less common.
Pathogenesis
MGN is caused by circulating immune complexImmune complex
An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex....
. The immune complexes are formed by binding of antibodies to antigens in the glomerular basement membrane
Glomerular basement membrane
The glomerular basement membrane is the basal laminal portion of the glomerulus. The Glomerular capillary endothelial cells, the GBM and the filtration slits between the podocytes perform the filtration function of the glomerulus, separating the blood in the capillaries from the filtrate that...
. 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
Complement membrane attack complex
The membrane attack complex is typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the alternative pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane...
(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
Nephrin
Nephrin is a protein necessary for the proper functioning of the renal filtration barrier. The renal filtration barrier consists of fenestrated endothelial cells, the glomerular basement membrane, and the podocytes of epithelial cells...
synthesis and distribution.
Morphology
The defining point of MGN is the presence of subepithelial immunoglobulin-containing deposits along the glomerular basement membraneGlomerular basement membrane
The glomerular basement membrane is the basal laminal portion of the glomerulus. The Glomerular capillary endothelial cells, the GBM and the filtration slits between the podocytes perform the filtration function of the glomerulus, separating the blood in the capillaries from the filtrate that...
(GBM).
- By light microscopy, the basement membrane is observed to be diffusely thickened. Using Jones' stainJones' stainJones' stain, also Jones stain, is a methenamine silver-Periodic acid-Schiff stain used in pathology. It is also referred to as methenamine PAS which is commonly abbreviated MPAS....
, 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 podocytePodocytePodocytes are cells in the Bowman's capsule in the kidneys that wrap around the capillaries of the glomerulus...
s 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 hyalinizedHyalineThe term hyaline denotes a substance with a glass-like appearance.-Histopathology:In histopathological medical usage, a hyaline substance appears glassy and pink after being stained with haematoxylin and eosin — usually it is an acellular, proteinaceous material...
.
- Immunoflourescence microscopy will reveal typical granular deposition of immunoglobulins and complement along the basement membrane.
Although it usually affects the entire glomerulus, it can affect parts of the glomerulus in some cases.
Clinical presentation
Some patients may present as nephrotic syndromeNephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....
with proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
, edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
with or without renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
. Others may be asymptomatic and may be picked up on screening or urinalysis
Urinalysis
A urinalysis , also known as Routine and Microscopy , is an array of tests performed on urine, and one of the most common methods of medical diagnosis...
as having proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
. A definitive diagnosis of membranous nephropathy requires a kidney biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
.
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.Immunosuppressive therapy
- Corticosteroids: They have been tried with mixed results, with one study showing prevention of progression to renal failureRenal failureRenal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
without improvement in proteinuriaProteinuriaProteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
. - ChlorambucilChlorambucilChlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
- Cyclosporine
- TacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
- CyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
- Mycophenolate mofetilMycophenolate mofetilMycophenolate mofetil is an immunosuppressant and prodrug of mycophenolic acid, used extensively in transplant medicine. It is a reversible inhibitor of inosine monophosphate dehydrogenase in purine biosynthesis, which is necessary for the growth of T cells and B cells...
Perhaps the most difficult aspect of membranous glomerulonpehritis is deciding which patients 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 patient will progress to end-stage renal disease, or renal 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 endstage renal failure. A meta-analysis of four randomized controlled studies 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. A small, randomized controlled study of 17 patients with a persistent nephrotic syndrome and declining renal function suggested that ciclosporin A slowed the rate of decline of renal function: this requires confirmation in a larger trial.
Natural history
About a third of patients have spontaneous remission, another third progress to require dialysisDialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
and the last third continue to have proteinuria, without progression of renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...
.