Question about nephritic vs nephrotic

[Pinkleton]

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Hey guys, I have a few points that i need confirmation/clarification on

From what I gather, preformed immune complexes deposit into the mesangium and/or subendothelial because of their large size. Since these areas have access to the glomerular blood supply, WBCs can be recruited --> inflammation --> nephritic?

For nephrotic syndrome, you have various free antigens that are small enough to reach the subepithelial space and deposit there. At a later point, for whatever reason, antibodies to these antigens (via molecular mimicry) are filtered from the blood through the glomerulus where they form complexes with antigens in the subepithelial space. Since this space does not have access to glomerular blood supply, there will be no inflammation (just effacement of foot processes) and hence a nephrotic presentation?

If all that is correct, here is what is confusing me. With post-streptococal glomerulonephritis you have the second scenario mentioned above and end up with subepithelial deposits. Why would the presentation be nephritic instead of nephrotic? I read in Goljan that these subepithelial complexes "activate complement" while other subepithelial complexes do not...how do they activate complement without "access" to the blood vessels?

I know this is likely more detail needed for step 1, but I need to understand the concept fully and would appreciate anyone's input! 🙂

 

[Pinkleton]

Anybody???

 

[JoshSt]

The simple:
Pathoma says that the deposits start out subendothelial and diffuse/extravasate out to being supepithelial.

The complex:
It is my understanding with nephritic syndrome that you have such a massive inflammation of the filtration unit that this leads to a decreased GFR. While you have enough permeability in nephritic syndrome for sheared RBC's to extravasate into Bowman's Space, you don't have as much proteinuria because of the reduced GFR.

To answer question of PSGN, pathoma says that the deposits start out subendothelial and diffuse/extravasate out to being supepithelial. Starting out sub endothelial, during their time there, the Fc portion of Ab in the Ag-Ab immune complex can fixate complement and this can damage the endothelial cells in two ways: 1) formation of the MAC and 2) C5a --> chemoattractant to PMN's which can also damage the endothelial cells. Whatever the cause of the endothelial damage, this will expose BM --> microthrombi. C3aC5a --> degranualation of mast cells --> histamine --> incr vasc permeability. The microthrombi will make sheared components of RBC's (what ends up in red cell casts) and the incr vasc perm via histamine will lead the sheared RBC elements to extravasate into the tubules. Again, no massive proteinuria because of the decreased GFR due to MASSIVE inflammation of the filtration unit.

The following is somewhat speculative: given that the immune complexes in PSGN start out subendothelial, perhaps they cause such increased vascular permeability and endothelial cell damage that they extravasate very, very quickly --> what is most appreciable of EM is the subepithelial deposits.

 

[Pinkleton]

The simple:
Pathoma says that the deposits start out subendothelial and diffuse/extravasate out to being supepithelial.

The complex:
It is my understanding with nephritic syndrome that you have such a massive inflammation of the filtration unit that this leads to a decreased GFR. While you have enough permeability in nephritic syndrome for sheared RBC's to extravasate into Bowman's Space, you don't have as much proteinuria because of the reduced GFR.

To answer question of PSGN, pathoma says that the deposits start out subendothelial and diffuse/extravasate out to being supepithelial. Starting out sub endothelial, during their time there, the Fc portion of Ab in the Ag-Ab immune complex can fixate complement and this can damage the endothelial cells in two ways: 1) formation of the MAC and 2) C5a --> chemoattractant to PMN's which can also damage the endothelial cells. Whatever the cause of the endothelial damage, this will expose BM --> microthrombi. C3aC5a --> degranualation of mast cells --> histamine --> incr vasc permeability. The microthrombi will make sheared components of RBC's (what ends up in red cell casts) and the incr vasc perm via histamine will lead the sheared RBC elements to extravasate into the tubules. Again, no massive proteinuria because of the decreased GFR due to MASSIVE inflammation of the filtration unit.

The following is somewhat speculative: given that the immune complexes in PSGN start out subendothelial, perhaps they cause such increased vascular permeability and endothelial cell damage that they extravasate very, very quickly --> what is most appreciable of EM is the subepithelial deposits.

Wow that is a tremendous explanation, thanks for taking the time to do that! And your speculation definitely would explain the findings.

So basically, PSGN starts off the same as the typical nephritic process involving immune complexes, but is unique in that it causes much more of an inflammatory response than other immune complexes. This results in a subepithelial appearance.

How about another nephritic case like IgA nephropathy, where IgA immune complexes form? Are only mesangial deposits found because there is comparatively less inflammation? Any idea what exactly about different immune complexes determines the degree of complement activation?

Again, thanks for the response as it definitely cleared this up for me

 

[JoshSt]

You are correct, there is basically less inflammation in IgA nephropathy --> less damage to endothelial cells, no/no significant complement activation --> not as much vasc perm b/c relatively less histamine. Why "just" the mesangium on IF in IgA --> the epithelial cells are not damaged (or as damaged) and the endothelial cells are more in tact. In PSGN there are IF deposits in the mesangium + elsewhere vs IgA they only cause enough damage to get the mesangium.

I do not know about different levels of complement fixations with different Ab subtypes (IgG, IgA, ect). I do know that the IgA molecules in IgA nephropathy are abnormal Ab molecules and there is normal serum complement levels. Perhaps its the abnormality in the IgA molecule that makes it not fix complement (or maybe IgA in general does not fix complement as well as IgG/M, I'm not sure). This doesn't answer your question but the following have low complement levels (taken from a PreTest book I believe): Membranoproliferative glomerulonephritis; Post-streptococcal glomerulonephritis; Essential mixed cryoglobulinemia; Lupus glomerulonephritis.

Thanks for the question, I appreciate the mini-review I had of these diseases in answering it.

 

[Work]

Perhaps its the abnormality in the IgA molecule that makes it not fix complement (or maybe IgA in general does not fix complement as well as IgG/M, I'm not sure).

You're right. IgA doesn't normally fix complement, but complement can be activated if there is aggregation. Only IgG/M can fix complement.