Nephritic Syndromes

We’ll start with a refresher of the Glomerulus and its structure & function. 

1. Basement Membrane
   1. Wraps around the whole capillary lumen except for the mesangial side which lets the larger molecules of the blood into the mesangium. 
   2. Composed of collagen IV (isomers α3 to α5), laminin, fibronectin, entactin, nidogen and heparin sulfate proteoglycan.
2. Endothelial Cells
   1. Single layer of fenestrated cells with a negatively charged surface.  The gatekeepers.
3. Epithelial Cells
   1. Adhered to outer aspect of the basement membrane via the podocyte foot processes.
4. Axial (Intracapillary) Mesangium
   1. Functions as capillary support, modulation of filtration, phagocytosis and makes factors

Moving onto the actual pathology.  Here’s a quick reference outline of the pathogenic mechanisms that we’re going to go over, all of them immunologic. 

1. Immune complex mediated
   1. Deposition of circulating immune complexes
   2. In-situ immune complex formation

                                                               i.      Anti-glomerular basement membrane antibody mediated

1.       Goodpasture disease

                                                             ii.      Heymann’s Nephritis

2. ANCA associated nephropathy – Small Vessel Vasculitis
   1. Wegener’s Granulomatosis (C-ANCA)
   2. Microscopic Polyarteritis (P-ANCA)
   3. Churg-Strauss Syndrome (P-ANCA)

The complex antigens can be:

1.       Exogenous antigens from infections, drugs or foreign particles

2.       Endogenous antigens from DNA, Ig’s, tumors.

In-situ immune complex formation causes glomerular damage by having antibodies react directly with antigens that have landed and gotten stuck in the glomerulus.  This can be divided into two categories:

AGBM Nephritis and Heymann Nephritis. 

1. Anti-glomerular basement membrane antibody induced nephritis

   
    

   1. Antibodies are directed against intrinsic fixed antigens that are normal components of the GBM.  
   2. Stay solely in the BM without reaching into the foot processes.

                                                               i.      Gives a linear immunofluorescent pattern without dense areas.

3. Can be caused by:

                                                               i.      Infections

                                                             ii.      Noxious environmental agents (solvent inhalation, smoking)

                                                            iii.      Secondary injury (transplant rejection, immune complex injury, ischemia)

4. The BM is a weak classical complement activator à complement will be normal or slightly lower
5. Goodpastures Disease:  an autoimmune disease with lots of neutrophils

                                                               i.      Antigen located at NC1α-3 locus antibody binding site.

1.       We know where it is but not what it is…yet.

2. Heymann Nephritis

   
    

   1. It was found that its specific antigens in the epithelial cells is gp-330/44
   2. Also, has antigens in the endothelial cells and mesangial cells

                                                               i.      For this reason complexes are found outside of the BM on the foot processes

3. These antigens can be:

                                                               i.      Autologous antigens such as your own DNA attacked in SLE

                                                             ii.      Heterologous antigens from bacteria or viruses

1.       Typically thought of to be strep but not common in the US anymore

ANCA (anti-neutrophil cytoplasmic antibody) associated nephropathy usually has to do with small vessel vasculitis.  In these diseases you see C3 and Properdin deposition (“Pauci-immune” granular pattern) which is an activation of the Alternate Complement Pathway.  (Contrast with AGBM Nephritis.)  Also remember we see petechial hemorrhages all over the kidneys in all the ANCA diseases.  There are three diseases where we see this:

1. Wegener’s granulomatosis – Proteinase-3 à C-ANCA positive

a.       In C-ANCA, you get immunofluorescence throughout the whole cytoplasm

2. Microscopic polyarteritis – Myloperoxidase à P-ANCA positive

3. Churg Strauss Syndrome – Myloperoxidase à P-ANCA positive

a.       In P-ANCA, you get immunofluorescence in the perinuclear space, not diffused.

We now get to the nephritic syndromes.  All the things above are the mechanisms which cause these to occur.  Think of what’s above the details and what’s coming below as bigger picture diseases.

Here’s a quick reference outline of the nephritic syndromes that we’re going to go over. 

1. Diffuse & Focal Proliferative Glomerulonephritis
2. IgA Related disorders

2. Primary IgA Nephropathy

                                                               i.      Berger’s Disease

                                                             ii.      Henoch-Schoenlien Purpura

3. Secondary IgA Nephropathy
4. Crescentic Proliferative Glomerulonephritis (Rapidly Progressing GN)

                                                               i.      Immunopathologic

1.       Type I: Anti GBM glomerulonephritis

2.       Type II: Immune-complex glomerulonephritis

3.       Type III: Vasculitis associated glomerulonephritis

Diffuse & Focal Proliferative Glomerulonephritis can be caused by all of the immunopathologic mechanisms we spoke about earlier.  Because of this, you can see a decrease in the complement system in both the classical and alternate pathways.  In regards to the clinical picture, they present similarly with FPGN being less severe then DPGN.  This is due to the fact that we usually start with FPGN and then progress to DPGN. 

IgA related disorders are the #1 cause of glomerular nephritis in the world and in Australia, its like everyone’s got it.  (That’s how you know you’re cool)  Dr. Khan seemed wrapped up with the fact that the incidence there is 25-45%, the highest in the world.  They are divided into primary and secondary nephropathies. 

1. Primary IgA nephropathy
   1. Berger’s Syndrome

                                                               i.      Can be just IgA or IgA with IgG or IgM.

1.       IgA are large and can’t pass the BM which gets them caught up in the mesangial cells

                                                             ii.      Will start as focal then slowly involve the whole kidney

1.       GBM is layed down where it shouldn’t à scarring

                                                            iii.      Only alternative complement pathway activation. (C3 & Properdin)

                                                            iv.      Generally slow progressing.

                                                              v.      Elevated levels of circulating IgA with or without complexes.

2. Henoch-Scholenlien Purpura

                                                               i.      Disease of children and young adults

                                                             ii.      Sometimes preceded by strep infection in some

                                                            iii.      Polyarteritis causes purpura in skin, joints, GI and on kidneys.

                                                            iv.      Usually benign with a 90% 10 year survival

2. Secondary IgA nephropathy
   1. Associated with cirrhosis, celiac disease, dermatitis herpetiformis, mycosis fungoides spondyloarthropathy, SLE, regional enteritis, CF
   2. Generally asymptomatic.

Crescentic Proliferative GN aka Rapidly Porgressive GN is a combination of diseases.  He made the analogy with secondary hypertension saying that it’s not caused just by one thing.  Think nephritis once benign, turned malignant.  It has three immunopathologic mechanisms we spoke up before:

1.       Type I: Anti GBM glomerulonephritis (15%)

a.       Elevating titers of Anti-GBM antibodies

2.       Type II: Immune-complex glomerulonephritis (35%)

a.       Circulating immune complexes

3.       Type III: Vasculitis associated glomerulonephritis (50%)

a.       Anti-neutrophil cytoplasmic antibodies

It can be seen with rapidly progressing renal insufficiency.  Its characteristic histological finding is Crescents of proliferated parietal epithelial cells and blood monocytes in the bowman’s space.  This is caused as a response to leaked fibrinogen and fibrin along with the increased synthesis of IL-1 and TNF.  All four of these are found to be increased in the blood.  50% of the glomeruli need to be crescent for diagnosis.  75% or greater is a bad prognosis.

Back to the Excretory System Index