Nephritic syndromes: Pathology review

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Case Study0:00–0:51

On the nephrology ward, two people came in with the same symptoms: peripheral and periorbital edema, along with cola-colored urine, arterial hypertension and decreased urine output.
The first person is 10 year old Timmy who had a throat infection two weeks ago. The second one is 45 year old Dorothy, who also presents with hemoptysis.
Lab tests show that both of them have increased creatinine and BUN. On urinalysis, there’s hematuria and red blood cell casts in the urine.
A 24-hour protein collection was done and showed that both Timmy and Dorothy had proteinuria, but in both cases it was less than 3.5 grams per day.
Now, both Timmy and Dorothy have nephritic syndrome. Nephritic syndrome is typically caused by inflammation that damages the glomerular basement membrane, leading to hematuria and red blood cell casts in the urine.

Pathology0:51–2:42

Eventually, this damage can lead to renal failure, where the individual can present with oliguria, arterial hypertension, due to sodium retention, and peripheral and periorbital edema.
Lab tests show high levels of BUN and creatinine and on urinalysis, there’s hematuria, proteinuria and RBC casts in the urine.
A 24-hour protein collection is necessary to quantify how many proteins are lost through urine. Now, nephritic syndrome can be differentiated from nephrotic syndrome because the proteinuria is generally under 3.5 grams per day, or within the “subnephrotic range”.
In severe cases though, proteinuria can reach over 3.5 grams per day. In order to determine the cause, a careful history and a kidney biopsy can help diagnose the particular disease.
Okay, let’s start talking about the different disorders that could cause nephritic syndrome. To make things simpler, we can categorize these into three groups; those caused by type III hypersensitivity, like poststreptococcal glomerulonephritis, IgA nephropathy, and Diffuse proliferative glomerulonephritis; those with multiple potential causes, like membranoproliferative glomerulonephritis, and rapidly progressive glomerulonephritis; and finally, Alport syndrome which is caused by a defect in collagen synthesis.
For the diseases that are only caused by a type III hypersensitivity reaction, let’s start with acute poststreptococcal glomerulonephritis or PSGN, which is most frequently seen in children, a very high yield fact.

PSGN2:42–4:55

Poststreptococcal glomerulonephritis can happen 2 to 4 weeks after a group A streptococcal infection of the pharynx or the skin, like impetigo.
Some group A streptococci strains carry the M-protein virulence factor, which initiates a type III hypersensitivity reaction where antibodies, often IgG and IgM, form immune complexes with the bacterial antigen.
These immune complexes travel to the glomerulus through the blood and deposit in the glomerular basement membrane or GBM.
Most of the time they’re subepithelial, meaning between the podocytes and the basement membrane. The immune complexes initiate an inflammatory reaction in the glomerulus, which involves activation and deposition of C3 complement, inflammatory cytokines, oxidants, and proteases that damage the podocytes.
For your test, remember that lab tests show low levels of C3 in the blood and strep titers and serologies are positive. Although a kidney biopsy isn’t always necessary, when it’s done, it can provide some specific clues.
On light microscopy, the glomeruli are enlarged and hypercellular. On immunofluorescence, there are IgG, IgM and C3 deposits along the glomerular basement membrane and the mesangium, which create a specific “starry sky” appearance.
On electron microscopy, there are subepithelial deposits which appear as “humps”. PSGN usually resolves on its own in children, but in adults, it can sometimes lead to renal failure, so another high-yield fact is that age affects prognosis.

IgA Nephropathy4:55–6:58

Next on the list is IgA nephropathy, formerly called Berger’s disease . This happens when abnormal IgA form in the body and the immune system recognizes them as foreign.
In response, the body generates IgG antibodies that target these IgAs, forming immune complexes which travel through the bloodstream and then get trapped in the kidney.
The immune complexes specifically deposit in the mesangium which is the tissue in the Bowman’s capsule that offers structural support to the glomerular capillaries.
The IgA-IgG immune complexes activate the alternative complement pathway, leading to the release of proinflammatory cytokines and migration of macrophages into the kidney, all of which contributes to glomerular injury.
What’s absolutely important to remember for your tests is that IgA antibodies are mainly secreted by the mucosal tissues of the respiratory and GI tract, so a high yield fact is that IgA nephropathy usually accompanies a respiratory or a GI infection.
On light microscopy, there’s mesangial proliferation. On immunofluorescence, there are IgA immune complexes in the mesangium and on electron microscopy, the immune complexes are again seen in the mesangium.
Okay, now your test might try to confuse you by presenting a similar disorder called IgA vasculitis, also known as Henoch-Schonlein purpura.
Remember, the difference is IgA nephropathy only affects the kidneys, while IgA vasculitis can cause nephritic or nephrotic syndrome, but it also presents with colicky abdominal pain, bloody stool, arthritis, and palpable skin lesions.
Let’s move on to Diffuse proliferative glomerulonephritis, which is often caused by systemic lupus erythematosus. Lupus is an autoimmune condition that affects multiple organs, including the kidneys.

DPGN6:58–8:24

This is another example of type III hypersensitivity reaction, where immune complexes are formed and deposit in various parts of the body.
Once they reach the kidney, they initiate an inflammatory reaction that leads to nephritic syndrome. Lupus nephritis is classified depending on the exact site of these immune complexes and subsequent inflammatory reaction.
With diffuse proliferative glomerulonephritis, diffuse means that more than 50% of the glomeruli in both kidneys are affected.The most common site of deposition is in the subendothelial space, meaning between the endothelial wall and the glomerular basement membrane.
On light microscopy, the immune complexes create an overall thickening of the capillary wall, which gives a “wire loop” appearance.
On immunofluorescence, there are granular immune complexes. On electron microscopy, you can see sub-endothelial immune complexes.
Okay, we’ve covered the conditions that are mainly caused by type III hypersensitivity reaction. Next we’ll talk more complex conditions that could have multiple causes.

MPGN8:24–12:30

First, there’s membranoproliferative glomerulonephritis or MPGN. There are actually three types of MPGN, but they all cause proliferation of mesangial and endothelial cells in the glomerulus.
We’ll only go through the first two, since the third type isn’t well understood. Type I MPGN is the most common form, and it can be idiopathic or secondary to hepatitis B or hepatitis C infection.
Type I MPGN usually starts one of two ways. The first way is through type III hypersensitivity reaction where there are circulating immune complexes made from antibodies bound to antigens released from hepatitis B or hepatitis C, infections, and this is another very high yield fact!
Over time, many of these immune complexes that circulate in the body reach the glomerulus and activate the complement system through the classical pathway, also causing complement deposition.
These immune complexes end up in the subendothelium, meaning between the endothelial wall and the glomerular basement membrane.
The second way is not caused by a hypersensitivity reaction, but it involves the inappropriate activation of the alternative pathway of the complement system.
With this pathway, C3 is converted to C3a and C3b by an enzyme called C3 convertase. Inappropriate activation of this enzyme could be caused by a genetic mutation, or a special IgG autoantibody, called “nephritic factor” or C3NeF.
This IgG binds to the C3 convertase, stabilising it and allows it to continue working. This “long-life” C3 convertase keeps on converting C3 to C3a and C3b.
This process consumes a lot of C3, so serum C3 levels are low. Since in this situation there’s inappropriate activation of complement, there are no immune complex deposits with the complement deposits.
Either way, in type I MPGN the immune complexes and/or complement deposits end up in the subendothelium. These immune deposits recruit inflammatory cells to the area, causing inflammation and damaging the glomerulus.
This in turn leads to the thickening of the basement membrane, which also triggers the mesangial cells to proliferate and reach through the thick basement membrane with their cytoplasmic arms.
This process is called mesangial interposition which sometimes causes the basement membrane to split around the mesangial cell, forming a duplication of the basement membrane or “tram-track” appearance on light microscopy.
Also because of the immune complexes or complement deposits, the glomeruli also appear granular on immunofluorescence. Okay, next we have Type II MPGN, which is also caused by nephritic factors but does not involve immune complexes.
It’s now classified as its own separate disease called dense deposit disease. Once again, this nephritic factor stabilizes the C3 convertase and allows it to keep on converting C3 to C3a and C3b.
In this case, complement deposits in the basement membrane as opposed to the subendothelium as in type I, which leads to inflammation in the basement membrane, and low circulating levels of C3.
MPGN shows the same tram-track pattern on light microscopy. Let’s move onto rapidly progressive glomerulonephritis or RPGN.

RPGN12:30–17:36

This is a very special type of glomerulonephritis that can be initiated by type II or III hypersensitivity reactions or sometimes, there are no immune complexes at all.
Here, the inflammation in the glomerulus is so severe, that it breaks the glomerular basement membrane and as a result, the kidney function decreases rapidly in a matter of days to weeks.
RPGN can be idiopathic, but when the cause is known, it can be split into three types. Type I is associated with Goodpasture disease and it’s a type II hypersensitivity reaction caused by anti-glomerular basement membrane, or GBM, antibodies that target the α3 chain of collagen type IV, in the GBM and the alveolar basement membrane.
Once these autoantibodies, usually IgG, bind to the α3 chain, they activate the complement system, which damages the basement membrane as well as the nearby endothelium and the underlying organ itself.
A similar process is also happening in the basement membrane of the lungs, and causes widespread damage to the alveoli, leading to hemoptysis.
Type II RPGN is another type III hypersensitivity reaction. Now, sometimes, with both poststreptococcal glomerulonephritis and diffuse proliferative glomerulonephritis, the, inflammation in the glomerulus is so severe that it causes the GBM to break, leading to RPGN.
Finally, there’s Type III RPGN, which is caused by pauci-immune vasculitis. Pauci-immune means there’s little or no anti-GBM antibodies or immune-complex deposits.
The two ANCA-associated vasculitis include granulomatosis with polyangiitis, or GPA, formerly known as Wegener’s granulomatosis, and microscopic polyangiitis.
Now, GPA classically affects the blood vessels supplying three organ systems: the upper respiratory tract, the lower respiratory tract and the kidneys.
Upper respiratory tract symptoms include chronic sinusitis, otitis media, mastoiditis, or even perforation of the nasal septum.
Lower respiratory tract symptoms include hemoptysis. On your exam, don’t confuse GPA with Goodpasture disease which also presents with lower respiratory tract symptoms and glomerulonephritis, but there’s no upper respiratory tract symptoms.
For GPA, c-ANCA antibodies are present and the histology would show non-caseating granulomas. Microscopic polyangiitis presents similarly to GPA, but upper respiratory tract symptoms are absent.
Remember that a unique feature is that microscopic polyangiitis is precipitated by medications, especially antibiotics like penicillin.
Also, remember that unlike GPA, p-ANCA antibodies are present, and histology does not show granulomas. Now, whatever the underlying cause is, the common feature for RPGN is rapid and severe injury that causes the glomerular basement membrane to break.
This allows material circulating in the blood like red blood cells, inflammatory mediators, plasma proteins, and fibrin to pass through into the Bowman space.
Following this flood of material, more monocytes and macrophages enter the Bowman space, as well as parietal epithelial cells.
The presence of all these foreign materials lead to the expansion of the normally-thin epithelial layer of cells into a thick, characteristic crescent-moon shape.
Now, with all three types of RPGN, light microscopy shows a crescent moon shape in Bowman’s space, which is mostly made up of fibrin.
Immunofluorescence patterns are different though. With Goodpasture disease, the immunofluorescence pattern will be linear, since antibodies bind to collagen of the glomerular basement membrane.
Treatment of Goodpasture disease involves plasmapheresis in order to get rid of these bad antibodies. With type II, the immune complexes randomly deposit in the subendothelial space, creating a granular pattern.
Finally, with pauci-immune vasculitis, you absolutely have to remember that immunofluorescence won’t show any immunoglobulins or complement deposition.
In this case, serum ANCAs are done to check for pauci-immune glomerulonephritis. Finally, let’s talk about Alport syndrome.

Alport Syndrome17:36–18:18

This is actually a genetic disease, where there’s a mutation in the gene that codes for type IV collagen. Without this type of collagen, the glomerular basement membrane becomes thin and splits.
Alport syndrome also causes hearing loss during late childhood or adolescence but the precise mechanism is unclear. Some patients with Alport syndrome also have retinopathy and lens dislocation.
On electron microscopy, the glomerular basement membrane appears irregularly thin in some areas. There are also areas where the glomerular basement membrane is thicker and creates a “basket weave” appearance.

Review18:18–19:27

Ok, let’s review! With nephritic syndrome, there’s inflammatory damage to the kidney that causes hematuria, peripheral and/or periorbital edema, arterial hypertension due to salt retention and oliguria.
Lab tests show high levels of creatinine and BUN, which means there’s also kidney failure. Urinalysis shows hematuria with red blood cell casts in the urine, along with proteinuria, that’s below 3.5 grams per day.
Nephritic syndrome can be caused by type III hypersensitivity reaction and this is the case for Poststreptococcal glomerulonephritis, IgA nephropathy and diffuse proliferative glomerulonephritis.
Other disorders can cause nephritic syndrome through multiple mechanisms like with MPGN and RPGN. Finally, there’s the genetic disease called Alport syndrome which affects collagen synthesis.
So remember! A careful history and a kidney biopsy are needed to determine the exact cause.
Coming back to our individuals, Timmy is a young boy who has had a throat infection 2 weeks prior to the renal manifestations, which is consistent with poststreptococcal glomerulonephritis.

Summary19:27–20:08

This usually resolves on its own and his prognosis is excellent. Then there’s 45 year-old Dorothy that presents with hemoptysis and oliguria which suggests Goodpasture disease.
Further investigations showed that anti-GBM antibodies were positive and the kidney biopsy showed the characteristic crescent shape seen with RPGN.
Regarding treatment, immunosuppressive therapy is the treatment of choice. ...And that’s the nephritic syndrome pathology in a nutshell.