Membranoproliferative glomerulonephritis

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.