Glomerulonephritis: what it does and how txt

This is the low-bandwidth, text alternative to the video Glomerulonephritis: what it does and how, from the post The spectrum of glomerulonephritis.

Glomerulonephritis: what it does and how

Neil Turner – Aug 2020

Here are ten glomeruli (by Beth Shortt), and you’ll remember that’s just enough to fit onto the head of a pin. We’ll cover here:

• Why important – how they present
• Normal structure: what’s to damage
• Proteinuria and haematuria: science
• Causes of glomerular disease (outline)

In other posts you’ll find enough info on individual diagnoses to come up with the most likely causes for key presentations, and answers to exam questions. Make sure you cover the three key posts referenced from the foot of  The spectrum of glomerulonephritis (the page this one was referenced from).

In setting the scene, it’s always worth relating things back that pre-renal, post-renal, and intrinsic-renal causes diagram of kidney diseases. It is relevant in approaching just about any kidney problem.

Here we’re dealing with intrinsic renal diseases, specifically glomerular diseases. But remember that the differential diagnosis of these conditions includes the interstitial conditions, and the systemic diseases – which mostly act through glomerular or interstitial routes. (sometime vascular/microvascular within the kidney)

It’s important

Glomerulonephritis is important because it’s a major cause of end-stage renal failure. Not only does it cause at least 25%+ of end-stage renal disease, but it’s a treatable cause. So it’s preventable end-stage renal disease.

When the glomerulus goes wrong

• It can leak protein, or it can leak blood.
• It can cause high blood pressure. That’s more prominent with some glomerular diseases.
• It can lose its fitration power (impaired kidney function).

Understanding glomerular damage

We’re going to show some  pathology sections. You certainly aren’t expected to become an expert renal pathologist, but understanding the basis of the things that are going wrong gives you a framework for understanding the diseases.

Each healthy kidney has about a million nephrons like this one with the glomerulus at the end doing filtering in each kidney. And they’re located out here in the real cortex, with this bit of the nephron and the collecting duct pointing down into the medulla. If you look at these in cross section, here’s a glomerulus, here’s another sitting in this sea of back to back, very healthy looking, beautiful tubules. Some of these are from the same nephron cut through again and again, and some of them are from neighbouring nephrons.

If you look at the cross section of the glomerulus itself, you can see it’s a nice open structure. This is a single glomerular capillary loop – here is another. And the glomerular basement membrane looks really quite nice and sharp, very similar in thickness or even thinner than the tubular basement membranes out here. That’s quite an important and useful differentiating sign.

You’ll notice that this particular glomerulus has been cut through the Macula Densa. It’s a subject of great interest to physiologists and important to function, so you may be disappointed that nephrologists don’t mention it so much. I’m afraid that we British nephrologists, who often get really excited by glomeruli, can be a disappointment to some of our North American colleagues, who get wide-eyed speculating about tubular physiology and electrolyte abnormalities.

Now let’s narrow down even further to just one corner of that glomerulus. Here we’ve got three capillary loops, and arrows pointing to the three different cell types of the glomerulus. First the endothelial cell – the nucleus is the only bit you can usually see inside the glomerular capillary loop, it’s smeared so thinly around the capillary. The podocyte on the other side of the glomerular basement membrane is a beautiful cell, which is incredibly important to the function of the glomerulus. And the third cell type is the mesangial cell. It’s kind of a macrophage-muscular-type cell with mixed functions, some unknown, in the middle of the glomerulus. If you saw this many together in one place, you would have an abnormal glomerulus, apologies for that in this diagram.

Now compare a real glomerulus. The endothelial cell nucleus sitts inside a glomerular capillary loop. The glomerular basement membrane (GBM) itself looks sharp, you could cut yourself on it, it’s thinner than the TBM out here. On the other side of the GBM, podocytes (again you can barely see cell bodies, mostly nuclei at this power if they’re healthy), and then the cells in the middle – mesangial cells. Three together is about as many as you’re supposed to get.

The clinical effects of glomerular disease, as so often in kidney disease in general, are often late and often nonspecific. Please have a look at the presentation of kidney diseases page and videos. Things to do with fluid in the wrong places, high blood pressure, and losing filtration power. Here we’re going to focus in particular on when the glomerulus leaks protein or blood.

Proteinuria and podocytes

The first of the two options is proteinuria. Occasionally patients see frothy urine, and they may mention this if they have very heavy proteinuria, but usually it’s something you’re going to pick up on dipstick. Just a reminder that the glomerulus is pretty impermeable to large molecular weight proteins; proteins much bigger than about 60 kDa are almost completely excluded at the glomerular filtration barrier. Which means that the protein which is most prolific in blood, albumin, is almost completely excluded from urine. Now I say almost because it’s not completely excluded, you can detect some in urine. Some is normally filtered and reabsorbed.

Proteins that are filtered at the glomerlus should be reabsorbed in the proximal tubule if it’s working properly. Therefore, if you see  low molecular weight proteins appearing which have filtered through the glomerulus, it implies that there’s something wrong with the tubules.

I’ve put immunoglobulin light chains on this slide, not because they are a very useful guide to normal kidney function, but if you start over producing these, they will be filtered. And many of these light chains are toxic to proximal tubules cells. That’s an important cause of pathology that we’ll see another time (see Myeloma).

We used to think that the GBM was a simple filtration membrane. But it turns out that the final frontier to protein is the foot processes of this very beautiful cell, illustrated looking down on it  from the urinary space, the podocyte. The processes of two different podocytes have been artificially coloured here. In particular, a very fine linear structure, the slit diaphragm, shown between the foot processes, appears to be very important. So if the podocytes loses its structure, either of the slit diaphragm or the overall  structure of its foot processes, proteinuria ensues. That’s an incredibly important sign clinically, proteinuria. It points to the nature of the underlying disease process.

At a high level of protein loss, heavy proteinuria indicates podocyte pathology. At a lower level, the cause of the proteinuria is less certain, because of the normal filtration of low molecular weight proteins, and the protein secreted into the distal tubule. Proteinuria is a really important diagnostic and prognostic indicator. And for reasons we don’t fully understand, it’s not only a prognostic indicator for kidney diseases, but also for cardiovascular outcomes, which is a fascinating (and inadequately explained) observation that needs drawing out elsewhere.

There is a lot of debate about whether proteinuria is such a good predictor of outcomes because it actually causes the long-term kidney damage, or whether it is it just an incidental indication that, for instance, the podocyte is sick. But because it is such a strong indicator of risk, proteinuria has become an attractive therapeutic target, either just to reduce it by some means, or to do something to protect the cell that causes it.

Haematuria and crescents

Leaking blood is slightly more complex, because blood can get into the urine at any level. So while proteinuria is mostly pointing towards disease in the kidney itself, haematuria can arise at any level in the urinary tract. Every textbook  has a diagram something like this, which shows all the possible points that blood can get into the urine:

The process of getting blood get into urine from the glomerulus is very different from getting protein there. In order to get a red cell from a glomerular capillary into the urinary space, you have to physically break open the glomerular basement membrane.

Here is one way you could do that.

On the left is a normal GBM. At the bottom here is the capillary lumen, and on the outside is Bowman’s space that the filtrate goes through. On the right is the same structure in a patient with Alport syndrome, which is a degenerative disease that affects one of the core components of basement membrane, Type IV collagen. It’s easy to see how blood would break through such a disrupted structure as this. But that is a very unusual cause.

 

This is much more common. Here we are now looking down on two rat glomeruli seen from the urinary space with all the cells taken off. All you can see here is the exposed glomerular basement membrane (GBM). On the right, the rat has been given a dose of anti-GBM antibodies, and by recruiting complement and cell-mediated immunity, holes have been blown into the GBM here. Now it’s easy to see how blood leaks out into the urine, and can form those beautiful red cell casts as it passes down the nephron.

So if it’s coming from the glomerulus, haematuria indicates holes in the GBM. But you have got to remember to ascertain that it is the kidney first. It’s usually inflammation that causes this.

Categories of causes of glomerular disease

There are some important

• Inherited (e.g. Alport)
• Metabolic (e.g. diabetes – numerically massive)
• Other

causes of glomerulonephritis, but most glomerulonephritis is (auto-)immune.

The evidence for this is that you can often see antibodies and complement deposited inside the glomerulus. You can see inflammatory cells recruited to fight the battle, and you can see that treatment for most types of glomerulonephritis is immunosuppressive regimens: steroids, immunosuppressive drugs, and so on. Most kidney diseases also have an animal model. In almost all cases, these are induced by immunizing or sensitizing to some glomerula antigen.

Now if it’s autoimmune, then there must be some target antigens. Here are some.

Anti-GBM disease is rare, but pretty well understood. You can see and indeed measure the cells of the immune system reacting to the target antigen in the GBM here. The antibodies in spontaneous anti-GBM disease are tightly targeted to specific epitopes in a tissue-specific component of basement membrane (type IV) collagen.

The podocyte can be damaged in various ways, but in membranous nephropathy it is targeted by antibodies binding to cell surface molecules. Several different antigens have been identified, but their clinical effect is similar.

In some conditions antigens might be planted in the kidney from elsewhere. So they might be from infectious agents, or they might, in the case of something like lupus, be autoantigens that are implanted (deposited or stuck) in the kidney.

Old textbooks may tell you that many diseases are caused by circulating immune complexes becoming trapped in the kidney. That does happen and there are some examples in the diagram. But actually it’s quite uncommon, it is more common for the antigen-antibody complexes to form in the kidney.

The endothelial cell is almost certainly the target of autoimmune attack in small vessel vasculitis, which is one of the important rapidly progressive destructive diseases. More on all these conditions in what follows.

The pattern of glomerular response points to what’s calling

Once there is an attack on the glomerulus, it only has a very restricted range of responses. It has three cell types and a GBM, and it can leak, it can cause high blood pressure, and it can lose filtration capacity. You can look at these patterns with very simple tests, and immediately sort out what the likely pathology is going to be. That’s the subject of the next short segment – see more in The spectrum of glomerulonephritis.