Haematuric diseases and crescentic nephritis txt

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Haematuric diseases and crescentic nephritis

Neil Turner – Aug 2020

So next, diseases at the right hand end of the spectrum that we were looking at before. Here we go so these are the conditions associated with inflammation and destruction and holes in the base of the membrane leading to hematuric manifestations.

There are three primary diseases and two systemic diseases which are dealt with in more detail elsewhere, and these are the ones we’re going to focus on.

Primary glomerular diseases

• Post-infectious/Strep (classic nephritic syndrome)
• IgA nephropathy
• Goodpastures (anti-GBM)

Systemic diseases

• SLE
• Small vessel vasculitis

But first, I want to talk a bit about the crescent. So at the very extreme end of the spectrum, there are the very rapid diseases that can quickly cause you to lose your kidney function altogether. The crescent that was in the image shown at the right hand side of the spectrum diagram is shown again here. It’s a proliferation of the epithelial cells lining bones capsule mostly, although it may include some podocytes sometimes as well. It grows in response to a leakage of fibrin from one of these holes in the glomerular basement membrane.

This beautiful picture on the left, you can see that this glomerulus has got some really badly destroyed areas of glomerulus here. This is a focal nephritis. You can see little bits of nuclear dust and dead cells in here and this pink stuff, fibrin leaking out into the urinary space here. This seems to be what stimulates the proliferation of the parietal epithelial cells to form this, and it’s presumably an attempt to repair damage and prevent the glomerulus from coming to complete disaster.

Here Jean, who has caught the very early stages of this happening in a glomerulus which looks otherwise pretty normal. Interestingly, if you defibrinate an animal you take away all of the circulating fibrin with snake venom you prevent this happening, but the glomerulus still gets destroyed.

So it’s not specific to any one disease and that’s important. It’s the aggressive phase of any of the diseases that cause glomerular hematuria. Therefore you could even get it in a severe example of alport syndrome, for instance, where there’s no inflammation at all and that does occasionally happen in animal models. But these are the conditions that cause it most frequently in clinical practice. Small vessel vasculitis, systemic lupus, and anti GBM disease which is rare but such a good example of renal information that we’re going to mention it. And any of the other conditions that can cause hematuria less commonly.

So this is anti GBM disease and here what you can see is a patient’s own antibodies, immunoglobulin G, bound to his, glomerular basement membrane. This was a young man who presented with lung hemorrhage because the same antigen is present in your lungs and had really quite normal looking kidneys at this time, except for the deposition of antibodies like this.

It’s a remarkable disease which can turn your glomerulus from looking like that to looking like this in a space of weeks.

Now this is a silver stain so that you can see the glomerular basement membrane is black. And even at this power, you can probably see the destruction of the glomerular basement membrane, it full of holes and the response of the surrounding epithelial cells has been to proliferate.

Now what you can see also in here, but not in detail at this power, there are breaks in Bowman’s capsule. This is a particularly bad prognostic sign. It seems to give access to fiber sites to move into this space. And that makes the crescent much less likely to recover. Other cells you’ll find in there include macrophages and other cells of the immune system.

Now the disease we’re illustrating here is rare. There’s probably a couple of cases per million per year in the UK. An instance which is probably creeping up slowly like a number of organ specific autoimmune diseases including insulin dependent juvenile onset diabetes. In this condition, we do know the target of auto-antibodies they bind to a tissue specific basement membrane collagen, the alpha 3 chain of type IV collagen. As I mentioned, this is present also in the alveolus and so this disease can present alternatively as a lung disease or as both together. And when that occurs both together with lung hemorrhage and renal disease, severe rapidly progressive renal disease, it’s called good pasture syndrome. Characteristically, very rapid deterioration of kidney function is condition and the biopsy we just looked at.

You can see that all of those glomeruli look as if they were affected at exactly the same time, something caused that disease to rev up very quickly. The treatment that was established in the 1970’s for this disease, and this mix of treatment has been used widely since actually is cyclophosphamide cytotoxic to kill lymphocytes and can B-cells in particular. Plasma exchange to remove the antibodies, cyclophosphamide prevents them re-synthesise and steroids to suppress the inflammatory response. It can be remarkably effective at arresting the kidney disease and lung disease if instituted early in the progression.

Now here is an example of a disease process that more commonly causes crescentic nephritis. This is what’s happening in the skin. So what do you think might be happening in the glomerulus?

Here’s a glomerulus and you might think that this segment in it, which looks highly abnormal, whereas much of the rest of this doesn’t look so very abnormal. You might think that this was FSGS, but look, this nuclear dust in here and this very pink stuff is necrotic tissue. So this is focal necrotising glomerular nephritis and the other clue that this isn’t just FSGS is the marked inflammation round about the glomeruli. Very commonly of severe glomerulonephritis will be accompanied by interstitial nephritis around it.

The picture on the right here is the one that was at the right-hand end of the spectrum diagram and shows a crescent. But this glomerulus at high power looks quite different, doesn’t it? So this is a glomerulus stuffed with neutrophils. You can also barely see any capillary loops partly because these cells are occluding them, but probably also because the endothelial cells themselves are proliferating and an attempt to react. This is associated typically with immunoglobulin deposition and it’s post streptococcal glomerulonephritis.

This is characteristic known as group A streptococcal infections, typically respiratory, but sometimes skin with a slightly longer delay after a throat infection. There is characteristically a ten day delay while the body mounts an immune response, which does this to the kidney. The exact molecular basis of this, not clear. Now than the nephritic syndrome that’s based on this is very widely known and because this was such a common disease, when nephrology was coming into being, this name of nephritic syndrome has tended to be applied to of all haematuric diseases, but let me comes back to that in a minute. If you do immunofluorescence on these biopsies, you can see immunoglobulin and complement deposition under the endothelium and under the epithelial cells, the podocytes was characteristically and low C3 compliment implying that it’s being consumed. And fluid retention in this condition is prominent.

It’s very interesting that some renal conditions cause fluid retention and high blood pressure much more prominently than others, basis of this not fully understood. But nephritic syndrome as defined by post streptococcal disease, of course, it always has hematuria. It also has proteinuria characteristically, which implies if in the full nephritic syndrome, which implies that podocytes are injured to again, the base about not fully clear. There’s really quite marked sodium and fluid retention as well as hypertension.

As indicated on the last slide, you can actually deal with this in children who are short of needing dialysis because this is typically an infection of children by diuretics.

But actually both patients in this biopsy were in their twenties on the left and late teens on the right. In the UK, it’s much more common to see this condition in older populations than worldwide when it’s characteristically a condition of children. Adults are also less likely to recover well.

So the third condition here is IgA nephropathy. This shows mesangial deposits central in glomerulus of immunoglobulin A in this quite protean condition.

So IgA nephropathy is one of the most common diagnoses we make when we’re investigating subacute glomerulonephritis. It’s pretty common worldwide actually, except in Africa. The reason there’s IgA in the mesangium is partially understood. It seems to be abnormal in that has less glycosylation than usual.

But again, not fully understood why that leads to this. It has quite a remarkable spectrum of presentations which we’ll just show in a minute.

This gives it its very long blurry arrow on this slide here. And quite characteristically this disease, we’ll start with a little bit of hematuria alone and move on to develop proteinuria as the disease progresses and in fact, as scarring develops. So it could prevent mild to severe. It can be asymptomatic hematuria to end stage renal disease, but characteristically its usually, not always, usually quite a slowly evolving disease over many years to decades even.

So most of the management is directed to protecting the kidney and slowing down the scarring processes. But in very acute disease, there is good evidence that steroids, but interestingly not other immunosuppressive agents can improve the outlook.

And this just indicates the presentations of IgA nephropathy. So Henoch-Schönlein purpura is a disease usually of children, which causes a skin vasculitis, a gut vasculitis or abdominal pain and hematuria.

Now the renal condition looks like IgA nephropathy, but with focal vasculitis, just like in the skin.

So it’s a variety of IgA nephropathy with vasculitis and the kidney is also affected by vasculitic like lesions in the small vessels in the glomerulus. That presentation becomes less common in late teens, and the most common presentation between, say, 15 and 30 is hematuria in association with respiratory infections. Now, unlike post streptococcal glomerulonephritis, the hematuria typically occurs at the time of the infection as opposed to after a 10-day delay and it may be recurrent.

Other patients don’t have either of these presentations and instead, abnormalities are picked up in their twenties, thirties, forties completely incidentally, sometimes. Incidentally they found out high blood pressure. Someone dip sticks their urine and finds hematuria and maybe proteinuria as well. And then the most common presentation a decade or two later is just with chronic kidney disease of unknown cause with hematuria and proteinuria.

So you may have two of these presentations or you may have just the one. It is a slowly evolving disease and it’s not clear whether you need to have had it all that time or whether it comes on later. So we’ve run through now the disease at this right hand end of the spectrum.

Except for one, we’ve now covered all the disease on this spectrum. So it’s only fair just to say a word about this condition in the middle.

MPGM Membranoproliferative glomerulonephritis known in the UK as Mesangiocapillary glomerulonephritis (MCGN) it’s the same condition. Now typically this gives you glomeruli that rather stiff and lobular and a characteristic change on silver stain is tram lining to double lines away are were you should see a single GPM. It’s particularly flagrant in this example on the right. This is actually caused by mesangial cells creeping around into the basement membrane. Mesangial interposition where they shouldn’t normally be. Now to be honest, it’s on that chart to fill a gap, it’s really quite complex.

If you want to know any more about it, there are four things that can cause this appearance and none of them are very simple. And the first one is infection. So it’s another potential response to infection. For instance, hepatitis C is quite a characteristic, cause of this, but many other subacute infections can cause this appearance. It can also occur in a variety of immune disorders and sometimes with monoclonal immunoglobulin deposition as well. Now both of these kinds will be associated with immunoglobulin deposition in the glomeruli, although with infection, that may fade, leaving mostly compliments and creating the issue of distinguishing it from the complement disorders which it causes. These are sometimes inherited, but sometimes autoimmune or, or other etiology disorders of complement regulation which cause this appearance and then you can get this appearance as a long-term consequence of thrombotic microangiopathy.

So best if asked about it, just to say, it’s very complex for the number of causes.

For glomerular diseases, it’s not all over, and there’s one more short section about this long-term impact of having had a glomerular disease this and others all available here: medcal.mvm.ed.ac.uk – Renal