Weatherly's Woes - Nephrotic

NEPHROTIC

Pissin' proteins

Nephrotic diseases all involve a leaky glomerulus that lets proteins out. The fundamental problem is that the electrical charge barrier breaks down. Their pee is voluminous and frothy. By losing proteins, the intravascular volume loses its osmolar pull, which results in diffuse peripheral pitting edema. So exactly which proteins are lost?

- - Albumin - most common protein. Maintains osmolality of blood. Without it, fluid leaks from the blood into the tissues. Patients get swoll all over (it’s easiest to perceive in the legs and around the eyes). The liver tries to compensate for the hypo-osmolar state by beefing up the blood with fats. So patients often have hyperlipidemia. This extra fat can spill into the nephron, coalescing into fatty casts.

- - Gammaglobulins - less antibodies → more infections

- - Antithrombin 3 - this natural blood thinning protein is lost in high numbers, leading to some hypercoagulability and clotting

MINIMAL CHANGE DISEASE

Minimal Change Disease was given its name because the damage it causes is subtle and difficult to visualize. The histology is normal! Until you use an electron microscope, that is. Looking at the glomerulus with an EM reveals flattening (or “effacement”) of the podocyte’s foot processes. Why does podocyte flattening result in protein loss? I’m not really sure. In general, there’s a lot that we don’t know about glomerular diseases.

MCD exclusively occurs in kids. It’s self-limiting and not especially dangerous.

We do know that cytokines mediate the podocyte damage. The majority of cases are idiopathic, usually following a cold or stomach bug. There are a few known conditions where circulating levels of cytokines are known to be high -- like Hodgkin Lymphoma. The Reed Sternberg Cells love to make cytokines (to recruit WBC’s to form their “tumor”). Note - while cytokines are involved, antibodies are not involved. Immunofluorescent staining is normal. The fact that cytokines are responsible is great news! That’s because we have great drugs for cytokines. MCD has an excellent response to good ol’ steroids.

The fact that the damage is hard to visualize should be an indication that the severity of protein loss is rather mild. Only smaller proteins are lost. Did you know that Albumin is 75x smaller than IgG? While albumin is lost in spades, gammaglobulins are not.

Normal (spiky)

MCD (no spikes)

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Focal (not every glomerulus is hit) Segmental (only part of the glomerulus is sclerosed) Glomerulo (glomerulus) sclerosis (scar)

We don’t understand the cause or MOA of FSGS. While most cases are idiopathic, some are seemingly secondary to another condition: HIV, Sickle Cell or heroin. FSG is the most common nephrotic syndrome in Black people. No good treatment. Electron microscopy reveals podocyte effacement (like Minimal Change disease). On test questions, expect to be asked about either the histology appearance (below) or the risk factors.

The right half is scarred.

MEMBRANOUS NEPHROPATHY

Membranous Nephropathy occurs whenever antibodies clog up the basement membrane of the glomerulus. It is the most common nephrotic syndrome in White people. MN affects those with No Melanin. There are 3 ways that antibodies can arrive there.

(a) Your body's own antigens (phospholipase A2) get stuck in the BM,

(b) Foreign antigens (hepatitis B) get stuck in the BM, or

(c) Already-bound antibody-antigen complexes (lupus) float through the bloodstream and accumulate in the BM (type 3 hypersensitivity).

The immune complexes are like buried landmines. They activate complement, which damages the BM, making it “leaky.” These landmines have a dome-like appearance (which is confusingly called a “spike and dome pattern”). The clusters can be seen on electron microscopy as dark balls, or on immunofluorescence as granules. The individual deposits can’t be seen under a normal microscope, but the overall BM looks thick and squiggly.

DIABETIC GLOMERULONEPHROPATHY

Diabetes can “fatten up” the mesangial cells and basement membrane. Mesangial cells are the supportive cells of the glomerulus. The current theory is that advanced glycosylated end products turn on genes that make these cells proliferate. In advanced cases (we’re talking decades here), you’ll see huge acellular pink blobs, called Kimmelstiel-Wilson nodules.

So the Mesangium gets bigger. And the BM gets bigger. Their growth spreads the podocytes apart, allowing proteins to slip through the cracks.

Note that Diabetic Nephropathy has several different components. Glomerulonephropathy is just one piece. One of the biggest players is hyaline arteriosclerosis of the renal arterioles, leading to hyperfiltration.

Kimmelstiel-Wilson Nodules

AMYLOIDOSIS

Amyloid is a clump of protein trash. These trash piles build up extracellularly. They damage healthy cells. There are ~40 different human proteins that can potentially turn into amyloid. The different proteins cause slightly different diseases. All amyloids share a common structural feature, β-pleated sheets. These sheets light up in the presence of the Congo Red Stain. You have to use a special stain, because Amyloid is simply pink on a normal H&E stain (similar to Collagen). The Congo Red Stain highlights Amyloid under both natural light (turning it pink) and polarized light (apple green birefringence). The best place to biopsy is abdominal fat.

Amyloidosis can affect pretty much every tissue in the body. Textbook symptoms include raccoon eyes (skin), big tongue (muscle), neuropathy (nerves), hepatomegaly (liver), malabsorption (gut), bleeding (vessels) and constrictive cardiomyopathy (heart). But the most commonly affected organ is the kidney. It leads to a Nephrotic syndrome.

Congo Red under normal light → pink blobs

Under polarized light → apple green birefringence

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Membrano (the BM is thick) proliferative (the mesangium undergoes hyperplasia)

MPGN is both nephritic and nephrotic. There will be 3+ proteinuria and 3+ hematuria. There are two types of MPGN. Type 1 is a lot more common. One of the defining characteristics of MPGN is that the mesangium expands into the BM and grows inside of it. This growth will occur in the center of the BM, splitting the BM in half. The double-line appearance is similar to the two metal rods of train tracks, hence the moniker “tram track” sign.

Type 1

Subendothelial deposits of IgG immune complexes (Granular immunofluorescence), which activates Complement. It’s usually idiopathic, but sometimes it’s caused by HepB or HepC infections.

Type 2

Patients make an evil antibody that targets the enzyme C3 Convertase. This enzyme activates the Alternative Complement pathway. The evil antibody, sometimes called C3 Nephritic Factor, actually overactivates the enzyme when it binds it. In this disease, the C3 Nephritic Factor binds to its antigen, and (for unknown reasons) deposits within the BM of the glomerulus. So predictably, the complement pathway gets turned on, and serum measures of C3 will be low. The BM is more affected in type 2 than in type 1. The BM becomes very thick in type 2, and is sometimes referred to as a “dark ribbon.”