Nephrotic/Nephritic disease and Alt vs classical pathway

[strive01]

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I always get tripped up on which one of the nephrotic and nephritic pathways use the alt complment (so low c3, normal C1, C4) and which ones use the classical pathway (low c1, c4?)

Would someone help clarify that for me? thanks 🙂

 

[Myxedema]

With the exception of MPGN type II, classical pathway activation will predominate. In MPGN type II, the autoantibody C3 nephritic factor will stabilize C3 convertase (C3bBb), which is an enzyme found in the alternative complement pathway.

Just to refresh, in the alternative complement pathway, C3 will be self-activated at first via microbial surfaces and factor B. Then, that C3 and factor B complex will be cleaved by factor D to form C3 convertase mentioned above. Thus, whether it is classical or alternative, ultimately a C3 convertase will form and cleave C3.

Now based on this, it is normal that when you have complement activation, whether classical or alternative, C3 levels will decrease. In various glomerular diseases, complement activation, again whether it is classical or alternative, will cause deposition of C3.

So at this point, you may ask: what it the difference? The difference is the steps preceding the formation of C3 convertase. Since alternative pathway creates C3 convertase via the mechanism described above, it does not use C1q, C4 or C2. Therefore, in MPGN type II, C1q, C4 and C2 levels can be normal and, perhaps more importantly, they won't be deposited in glomeruli. You can compare it with MPGN type I, where deposition of C1q and C4 will be seen.

Summary: C3 is decreased in most GN, including MPGN type II. MPGN type II mainly results in the activation of alternative complement pathway. Because of this reason, early complement components in classical pathway, such as C1q and C4 can be normal and they won't be seen in depositions under fluorescent microscopy.

 

[strive01]

that was a solid explanation - thank you!

my notes from uworld says that acute poststrep glomnephritis also activates the alt pathway and that c4 would be normal? i could have very easily just written that in the wrong place or something
what are your thoughts on acute poststrep glom and the alt pathway

 

[Myxedema]

I went back and checked Robbins, and it does not specifically mention alternative complement activation for APSGN. I see no reason why classical system shouldn't be activated APSGN, so I'd expect depletion of C1q and C4. I think MPGN type II --> alternative; the rest --> classical dichotomy is a good enough summary.

In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cola-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients have red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. In adults the onset is more likely to be atypical, such as the sudden appearance of hypertension or edema, frequently with elevation of BUN. During epidemics caused by nephritogenic streptococcal infections, glomerulonephritis may be asymptomatic, discovered only on screening for microscopic hematuria. Important laboratory findings include elevations of antistreptococcal antibody titers and a decline in the serum concentration of C3 and other components of the complement cascade.