View source for 19. Glomerulonephritis. Classification according to clinical symptoms. Histologic alterations in glomerulonephritides.

=== Introduction ===
''Glomerulonephritis'' (<abbr>GN</abbr>) or ''glomerular disease'' is a group of diseases where the glomeruli are damaged, although inflammation itself (-itis) is not necessarily present.

Glomerular damage is commonly caused by immune-mediated processes but can be caused by other processes as well, as we’ll see. All glomerular diseases can progress to acute or chronic renal failure, so quick diagnosis and immediate initiation of therapy is important.

Damage to the glomeruli may cause components of the blood that aren’t supposed to be in the filtrate to start appearing in the urine, like proteins and red blood cells.

The specific subtypes of GN are described in the next topics.

=== Etiological classification ===
We distinguish primary and secondary glomerular diseases. Primary diseases are those where the kidney is the only or predominant organ involved. Secondary are those where the GN is just a manifestation of a systemic disease like diabetes.
{| class="wikitable"
!Primary glomerular diseases
!Secondary glomerular disease
|-
|Minimal change disease
|Lupus nephritis
|-
|Focal segmental glomerulosclerosis
|Diabetic nephropathy
|-
|Membranous nephropathy
|Amyloidosis
|-
|Poststreptococcal glomerulonephritis
|GN secondary to multiple myeloma
|-
|Membranoproliferative glomerulonephritis
|Goodpasture syndrome
|-
|
|Microscopic polyangiitis
|-
|
|Granulomatosis with polyangiitis (Wegener’s)
|-
|
|Henoch-Schönlein purpura
|}

=== Nephrotic and nephritic syndrome ===
Nephrotic syndrome and nephritic syndrome are possible clinical manifestations of glomerular disease. Nephrotic syndrome refers to the presence of significant proteinuria (among other things), while nephritic syndrome refers to the presence of significant haematuria (among other things). These syndromes are further explained in the next topics.

We can classify glomerular diseases according to whether they ''usually'' cause nephrotic or nephritic syndrome:
{| class="wikitable"
!Generally causes nephritic syndrome
!Generally causes nephrotic syndrome
|-
|Poststreptococcal glomerulonephritis
|Minimal change disease
|-
|<abbr>IgA</abbr> nephropathy
|Focal segmental glomerulosclerosis
|-
|Granulomatosis with polyangiitis (Wegener’s)
|Membranous nephropathy
|-
|Goodpasture syndrome (anti-GBM disease)
|Membranoproliferative glomerulonephritis
|-
|Rapidly progressive glomerulonephritis
|Diabetic nephropathy
|-
| colspan="2" |Lupus nephritis
|}

=== Pathogenesis ===
GN is commonly caused by one or more of these three mechanisms:

# Deposition of circulating soluble immune complexes (antigen-antibody complexes) in the glomerulus
# Circulating antibodies that form immune complexes in the glomerulus by targeting antigens in the glomeruli (in situ immune complex formation)
# Circulating antibodies against the glomerular basement membrane

In all three cases will the presence of immune complexes in the glomeruli cause local inflammation. Let’s look at the mechanisms in more detail.

Mechanism 1: The glomerulus in this case can be considered an innocent bystander. The body responds to a circulating antigen by producing antibodies against it. The immune complexes that form travel with the circulation and deposit in the small vessels of the glomeruli where they become trapped. The trapped immune complexes initiate local inflammation.

The antigen that triggered the immune response can for example be:

* Of endogenous origin – in case of <abbr>SLE</abbr>
* A protein from streptococcus – in case of poststreptococcal glomerulonephritis
* A protein from Hepatitis B or C

In many cases the inciting antigen is unknown.

Once the immune complexes are deposited in the kidney they will be phagocytosed by immune cells. This eventually causes the inflammation to subside. This commonly occurs after poststreptococcal GN for example. If, however, the body is continuously exposed to the antigen, so that new immune complexes are formed and deposited continuously the inflammation will never subside and instead lead to chronic glomerulonephritis. This occurs when the antigen is endogenous (such as in SLE) or in chronic infections like hepatitis B and C.

Mechanism 2: The glomerulus in this case is not a simple bystander because the antibodies are actively targeting glomerular antigens or circulating antigens that have been planted in the glomerulus. This causes the immune complexes to form “on site” (in situ). These immune complexes initiate local inflammation.

Antigens that are commonly planted in the glomeruli are DNA (in SLE), bacterial, viral and parasitic products, drugs, cationic molecules and large aggregated proteins.

Mechanism 3: Autoantibodies against the glomerular basement membrane (GBM) is the pathomechanism behind ''anti-GBM-antibody-mediated disease'', also known as Goodpasture syndrome.

Mechanism of injury: In all mechanisms there will be immune complexes in the glomeruli. The deposited immune complexes activate the complement system which initiates inflammation and recruits inflammatory cells as part of a hypersensitivity type III. The leukocyte infiltration stimulates proliferation of endothelial, mesangial and parietal epithelial cells.

Neutrophils release proteases which degrade the glomerular basement membrane. Oxygen-derived free radicals secreted by the same cells cause damage to cells. Arachidonic acid metabolites like thromboxanes reduce the <abbr>GFR</abbr>.

In some types of GN only a few neutrophils are present. Most damage is caused by the complement system instead. The membrane attack complex (MAC) damages epithelial cells and stimulate them to produce inflammatory mediators.

Damage to the podocytes prevents these cells from maintaining the normal “selectivity” of the glomeruli. The glomerular slits may be lost, which may be important in the development of proteinuria in glomerulonephritis.

=== Diagnosis and histological alterations ===
Using immunofluorescence, light microscopy or electron microscopy to examine kidney biopsies is important in the diagnosis of glomerulonephritis. The different mechanisms mentioned above produce different patterns of immune complexes on immunofluorescence.

Several different terms may be used to further describe the different types of GN based on histology:

* Diffuse – all glomeruli are affected
* Focal – only a number of glomeruli are affected
* Segmental – only part of the glomerulus is affected
* Proliferative – cell proliferation in the glomerulus is involved
* Sclerosing – there is scarring in the glomerulus
* Necrotizing – there is cell death in the glomerulus
* Crescentic – cells like macrophages and fibroblasts accumulate in the Bowman’s space

Several abnormalities can be seen with simple light microscopy as well. The three most important are:

* Hypercellularity and inflammation
* Thickening of the basement membrane
* Hyalinization and sclerosis of the glomeruli

The hypercellularity occurs due to the proliferation of mesangial, endothelial and parietal epithelial cells. Leukocytes may be visible; the mechanism of inflammation was described above. In some cases the proliferating cells can form a “half-moon” structure as they occupy part of the glomerulus. This is called ''crescent'' formation and is characteristic for rapidly progressing glomerulonephritis (RPGN) and can be seen on the RPGN slide.

Thickening of the basement membrane occurs in diabetes as the endothelial cells take in more glucose and therefore produce more glycoproteins. It also occurs without diabetes due to materials being deposited in it, like immune complexes, fibrin, amyloids or cryoglobulins. The thickening is especially visible with PAS staining.

Hyalinization and sclerosis occur due to deposition of eosinophilic, homogenous material in the mesangium. These are the end-result of various kidney injuries.
[[Category:Pathology 2 - Theoretical exam topics]]