Complement component 3

Well, I think part of the surprise is the fact that when we check complement levels in the blood for these patients, we typically don't see any variance in the values.

We don't see low C3, low C4 like you would in a lupus patient.

Having said that, we shouldn't be as surprised.

If you biopsy a patient with IgA nephropathy, in about 90% of biopsy cases, you do see C3 deposited in the tissue.

Again, suggesting that there is complement activation and it's pretty obvious.

And we have a lot of data, even clinical data in humans that support the role of complement in IgA.

There's also serologic data that the complement system plays a role and is activated.

As I mentioned, the levels are typically normal.

Membrane cofactor protein, also called CD46, protects host cells by supporting factor I mediated complement regulation.

Complement factor B and complement factor C3 also play important roles in the activation and amplification cascade.

When complement regulation fails, the alternative pathway C3-convertease becomes excessively active.

This drives additional complement activation and ultimately increases formation of C5-convertease and the terminal complement complex C5B9, also known as the membrane attack complex.

Excessive terminal complement activation damages endothelial cells.

This explains the classic triad of HUS, microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.

Genetics is important, but it is not the whole story.

Some patients have pathogenic variants involving complement factor H factor I, factor B, C3, or membrane cofactor protein.

I don't move forward until as I've got the report of the serum complements.

So C3 and C4.

C3 tells me whether alternative pathway is being active or not, and alternative pathway is usually kind of complement, uh, dysregulation, either, uh, in intrinsically or in the presence of an active infection or malignancy, which is kind of leading the cascade activity all the time.

And C3-- and the C4 is usually classical pathway, so that's kind of your classical antigen-antibody complexes like lupus, infections, uh, cryoglobulinemia.

These are the things considered when you have got a low C4.

If you've got both low C3 and C4, focus more on the classical pathway.

There's a third pathway, lectin pathway as well, which is used in the setting of chronic infection.

So if you've got low C3, there's a certain differential diagnosis.