Wikipedia:Osmosis/Membranoproliferative glomerulonephritis
Author: Tanner Marshall
Editor: Rishi Desai, MD, MPH
Membranoproliferative glomerulonephritis, or MPGN, is a kidney disease triggered by immune deposits which end up in the walls of the glomerulus, which are the tufts of capillaries where blood is filtered. These deposits lead to inflammation and result in structural changes to the glomerulus, that cause a decrease in kidney function, which commonly presents as a nephrotic syndrome. But what exactly is nephrotic syndrome? Well usually the glomerulus only lets small molecules, like sodium and water, move from the blood into the kidney nephron, where it eventually makes its way into the urine. But with nephrotic syndromes, the glomeruli are damaged and they become more permeable, so they start letting plasma proteins come across from the blood to the nephron and then into the urine, which causes proteinuria, typically greater than 3.5 grams per day.
An important protein in the blood is albumin, and so when it starts leaving the blood, people get hypoalbuminemia—low albumin in the blood. With less protein in the blood the oncotic pressure falls, which lowers the overall osmotic pressure, which drives water out of the blood vessels and into the tissues, called edema.
Finally, it’s thought that as a result of either losing albumin or losing some protein or proteins that inhibit the synthesis of lipids, or fat, you get increased levels of lipids in the blood, called hyperlipidemia.
Just like the proteins, these lipids can also get into the urine, causing lipiduria. And those are the hallmarks of nephrotic syndrome—proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria.
Okay so membranoproliferative glomerulonephritis is a type of nephrotic syndrome, got it. But how exactly do these glomeruli start letting plasma proteins like albumin through? Well, with MPGN, there are actually three types, so let’s go through one by one. Type I MPGN is the most common form, and it usually starts one of two ways. The first way involves circulating immune complexes, made up of antigens and antibodies, that might form, for example, because of antigen release from a chronic infection like hepatitis B or hepatitis C which gets bound by antibody in the blood. Over time, many of these immune complexes might find their way to the glomerulus, and they cause an activation of the classical complement pathway, leading to complement protein deposition right along side the immune complex deposits.
The second way involves the inappropriate activation of the alternative pathway of complement. Specifically, with this pathway, C3 is converted to C3a and C3b by the enzyme C3 convertase. Inappropriate activation could mean a mutation in or autoantibody against proteins that regulate this process. On the flip side, since C3 convertase usually only exists for a short time, there could also be inappropriate activation if there is an IgG antibody that actually binds to C3 convertase, which makes the C3 convertase more stable, causing it to exist for longer periods of time, which means it keeps on converting C3 to C3a and C3b. This special IgG autoantibody is called “nephritic factor” (or C3NeF), and is responsible for some of the cases of type 1 MPGN. Since in this situation there’s inappropriate activation of complement, there are no immune complex deposits with the complement deposits.
Either way, the actual mutation or autoantibody triggering all this trouble isn’t always known, but what is known, is that the immune complexes and/or complement deposits end up in the subendothelium, meaning between the endothelial layer and the basement membrane of the glomerular capillaries. These immune deposits recruit inflammatory cells to that area which release oxidants and proteases that damage the capillary wall.
In addition to all this, that inflammation triggers the thickening of the basement membrane, which also triggers the mesangial cells of the glomerulus start to proliferate or divide and reach through the thick basement membrane with their cytoplasmic arms.
This process is called mesangial interposition which sometimes causes the basement membrane to split around the mesangial cell, forming a duplication of the basement membrane or “tram-track” appearance on light microscopy. Also because of the immune complexes, the glomeruli also appear granular on immunofluorescence.
Okay so type II MPGN generally involves only complement deposits and does not involve immune complexes, and actually is now classified as its own separate disease called dense deposit disease. The leading mechanism causing Type II MPGN is the same IgG autoantibody called nephritic factor that we talked about in type 1, except now this mechanism is responsible for nearly all of the cases. Once again, this nephritic factor stabilizes the C3 convertase and allows it to keep on converting C3 to C3a and C3b. In this case, complement deposits in the basement membrane as opposed to the subendothelium as in type I, which leads to (1) inflammation in the basement membrane, and (2) low circulating levels of C3. Most cases of dense deposit disease don’t show the same tram-track pattern, and it’s not quite clear how these complement abnormalities induce changes in the glomeruli.
Alright so finally we’ve got type III MPGN, but this guy is shrouded in even more mystery. This type seems also to be an immune complex and complement disease like type I, but in addition to finding deposits in the subendothelial space, there also seems to be deposits in the subepithelial space, though again, many of the mechanisms leading to glomerular changes aren’t well understood.
Regardless of the differences between these three types of MPGN, they can all present as nephrotic syndrome, usually characterized by proteins in the urine, but in addition to this they can also present as nephritic syndrome, since they all also involve some sort of inflammation, with characteristic findings of hematuria—or blood in the urine, oliguria—abnormally low production of urine, azotemia—increased nitrogen-containing compounds in the blood, and hypertension.
For treatment sometimes steroids may be given to suppress the immune system, although responses have been inconsistent, and all three types of MPGN can progress to chronic renal failure.
Alright, so super quick recap: type I MPGN is caused by either immune complex or complement deposits in the subendothelium, type II MPGN, or dense deposit disease, is when complement deposits are found in the basement membrane, and type III MPGN is where immune complexes or complement deposits are found in the subepithelium as well as possibly the subendothelium. All three typically lead to nephrotic symptoms, but occasionally nephritic symptoms as well.
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Sources
[edit]http://www.ncbi.nlm.nih.gov/books/NBK1425/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887509/
https://wiki.riteme.site/wiki/Membranoproliferative_glomerulonephritis