Proteinuric diseases and Nephrotic Syndrome txt

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Proteinuric diseases and Nephrotic Syndrome

Neil Turner – Aug 2020

We are going to look at diseases at the left-hand end of this spectrum, that cause proteinuria and nephrotic syndrome. Nephrotic syndrome is just a consequence of extreme proteinuria.

Nephrotic syndrome

Let’s first look at nephrotic syndrome itself.

This is a topic examiners love, because it’s so easy

to ask good questions about it. To patients it’s the difference between having elephant legs on the left and gazelle legs on the right. Young people often show it first in face and ascites though.

Nephrotic syndrome has slightly variable diagnostic criteria, but it doesn’t really matter how exactly you fit this description. Something like:

• Heavy proteinuria, more than 3.5 grams a day, or > 350 mg/mmol (internationally also expressed as 3.5 g/g or 3500 mg/g)
• Associated with a low serum albumin
• Accompanied by oedema

Particularly in young patients, it usually takes a lot more proteinuria than that to drop the albumin by very much. In the absence of low serum albumin or oedema, proteinuria at this level may be termed ‘nephrotic range’. Its causes are the same.

Complications

Nephrotic syndrome is associated with a variety of complications. Each gets more likely as proteinuria increases:

• Oedema (really a manifestation. So 3 complications.)
• Thrombosis
• Infection
• Hyperlipidaemia

Oedema is primarily caused by retaining salt in the kidney, in response to proteinuria. Rather than by low serum albumin, and that’s a very interesting and deep discussion for more detail elsewhere. But if it’s caused by salt retention, the treatment should be salt restriction, plus diuretics which increase sodium excretion. Of course if you don’t sodium restrict at the same time as you’re using diuretics then you’re struggling uphill.

Thrombosis: There is a substantially increased risk of thrombosis. Venous thrombosis and pulmonary embolism are common at presentation: the risk is particularly increased in the early phase of the syndrome. Some nephrologists anticoagulate beneath some magic level of albumin, while others are more cautious. Certainly maintaining safe INR ratios with warfarin can be a real problem in nephrotic patients. But that’s also an interesting deeper discussion.

Infection risk may be partly down to having low immunoglobulin levels, lost in urine, but may have other aspects to it as well. Particularly with encapsulated organisms, rather like patients with splenectomy. So immunization with pneumococcal and meningococcal vaccines is valuable if the syndrome is continuing. The role of penicillin prophylaxis is not so certain.

Hyperlipidaemia: It is also associated with extremely high levels of cholesterol, not uncommonly >10 mmol/l. And known long term risk of arterial disease as well as venous thrombosis. So although there’s no hard evidence of benefit from statins (HMG CoA reductase inhibitors) in nephrotic syndrome itself, the levels are so high that pretty much everybody with sustained nephrotic syndrome gets started on statins. These have been shown to be safe and to improve cardiovascular outcomes in the broader group of patients with CKD.

Causes: It’s the podocytes

Now to discuss three primary conditions. All cause pure nephrotic syndrome, you don’t expect haematuria:

• A disease that switches off the protein barrier at the glomerulus, on and off.
• A disease of dead podocytes.
• A disease of autoimmunity to podocytes .

And two systemic diseases that are associated with deposition of material in the glomerulus. You may just get a bit of haematuria with the systemic deposition diseases, but it’s usually low-level or absent.

• Diabetes – at least 10y usually, gradual progression from microalbuminuria
• Amyloidosis – AL, AA, and some rarer variants

Both of them upset the architecture of the glomerulus, so that the podocytes are sitting on some very unfamiliar surfaces and molecules, which deranges their function so that they do not maintain the protein barrier.

AND – important to remember that the same happens when scarring from any of the more destructive types of nephritis leave abnormal molecules and structure in the glomerulus. These too will cause proteinuria, and sometimes nephrotic syndrome. This means that any kind of inflammatory glomerulonephritis can cause some proteinuria, and may cause levels of proteinuria high enough to be defined as nephrotic syndrome.

Now to look in a little bit more detail at these three primary conditions that cause pure nephrotic syndrome.

Biopsy 1

I wonder what you think about this one. It is in fact, the normal glomerulus that we’ve used elsewhere. Beautiful open capillary loops. Actually there’s nothing you can say is wrong with it at all. And this is typical in a patient with nephrotic syndrome of minimal change disease.

Minimal change disease

If you look by electron microscopy, you don’t get these scanning EM pictures in a diagnostic biopsy. This view is looking down from the urinary space, onto the podocytes which are wrapped around the GBM in the capillary loops. On the left is normal, and on the right is nephrotic syndrome. Now if there are no other light microscopy changes, this can only be minimal change disease, where the only difference is that the beautiful fine interlocking finger structure of podocytes has been lost.

On transmission electron microscopy these are the beautiful foot processes of a podocyte, and here that structure is lost and they are fused. This is exactly what happens in minimal change disease. Something affects the podocyte to derange its structure and proteinuria begins immediately.

Here it is a rat’s glomerulus, and on the right is shown the rapid effect of administering an antibody that disrupts the slit diaphragm structure between foot processes.

Minimal change disease is usually steroid responsive and it does not progress to kidney failure.

As you can see within a couple of weeks in children, the proteinuria is going into remission, whereas adults with this condition respond more slowly and may require higher dose and longer treatment with steroid. But it’s very interesting that steroids can switch off this condition and when you stop the steroids, it is frequently a relapsing condition, but many patients don’t relapse, particularly the older patients. Children commonly have a relapsing, remitting disease and that can occur at any age, but you can remain free of proteinuria on no treatment at all until something happens to trigger the disease again. There are second line treatments to prevent relapses.

Children tend to respond more quickly, and it is the dominant diagnosis in children in Western/Northern nations who develop nephrotic syndrome. So the first intervention will often be a trial of steroids rather than a kidney biopsy as the initial intervention. But I should just mention that this is one of the diseases with some international variation in frequency.

Biopsy 2

As is the subject of Biopsy 2. This quadrant of the glomerulus, round about nine o’clock, looks pretty much  normal, as is the smaller segment opposite it. Whereas down  at six o’clock, there’s a region of far too much pink, but not much else happening. This is a sclerotic segment. It’s not filled with inflammatory or apoptic cells, it’s just more pink matrix. You can see here it’s adhering to Bowman’s capsule.

So that’s FSGS, by which we mean a disorder which is focal (in some glomeruli but not others). It’s segmental (affects part of the glomerulus at first). And it’s sclerosis, it’s not an inflammatory process. Focal segmental glomerulosclerosis, FSGS.

So all FSGS means is little scars in some glomeruli, and this can have various causes. So you can’t make a final diagnosis on just pathology, you need additional information.

All the causes of FSGS (coming shortly) typically cause pure proteinuria, and often nephrotic syndrome. But when people mention FSGS as a cause of nephrotic syndrome, they are often meaning Primary FSGS, in other words idiopathic, we don’t know the cause, but it does have some clear characteristics:

Primary FSGS

• Causes a severe nephrotic syndrome.
• Much less likely to be steroid responsive than minimal change disease
• More likely to progress to end-stage renal failure, typically some, but not too many years
• Can recur after renal transplantation, sometimes within hours.

That last observation implies that there is some circulating factor affecting podocytes – the factor is still not identified. It’s pretty devastating if FSGS does recur after transplantation as the treatments for it have limited effectiveness.

Other causes of FSGS

Direct podocyte damage

• Genetic, toxic
• HIV infection, parvovirus

Old injury

• Previous vasculitis
• Previous microthrombi, microemboli
• Other conditions

Reduced nephron number

• Congenital, obesity

So some of these things involve direct podocyte damage. We mentioned genetic causes of nephrotic syndrome elsewhere – these area almost always podocyte gene mutations, and typically present in infancy or early childhood. Then there are some toxins, some drugs – high-dose pamidronate, for instance, can do this. And then there are some infections, HIV infection, Parvovirus, and it’s also becoming suspected for COVID-19.

However scars could also just reflect previous injury to a glomerulus. For instance, if you have something affecting the small vessels in the glomerlus that leaves little scars, it could be that, it could be previous little from thrombi or microemboli for instance, arising from atherosclerotic plaques in renal artery. And other renal conditions can cause this kind of appearance fairly non-specifically.

Then there’s a group of patients with reduced nephron number or at least reduce nephron number compared to their size. So for instance, premature or low birthweight infants, including babies of malnourished mothers are more likely to get FSGS. And so are patients with gross obesity. In these circumstances, the treatment is our generic ‘nephroprotective’ treatment – see the info on Progression of Renal Disease.

International variation and genetics in FSGS

This is another of the conditions with marked international variation. FSGS is a much more common diagnosis in Africa, for instance – but also much more common in black Americans. And unusually we have a genetic explanation for this.

By tracking different nucleotide polymorphisms typical of recent African ancestry in patients in the US, it was possible to associate DNA regions conferring susceptibility to FSGS with particular DNA segments, and later to the specific gene ApoL1 encoding Apolipoprotein L1. This appears to be involved in resistance to Trypanosomiasis, and the variants have historically presumably been selected for in some regions of Africa. The penalty appears to be increased susceptibility to renal disease in people who have two copies of these sequence variants. Remarkably this genotype appears to almost entirely explain susceptibility to classic HIV nephropathy; plus the excess of FSGS, and the major part of the increased incidence of end stage renal disease previously identified in black Americans. The excess of ESRF had been mostly labelled ‘hypertensive’ – wrongly, if renal disease comes first. Interestingly, proteinuria is not generally said to be prominent. Mechanism still not clear.

Although several other conditions show marked international variation in incidence, this is the only example in which a simple, single-gene explanation has emerged. And it’s getting late for the others.

Biopsy 3

Now this glomerulus looks much too pink. And looking at the capillary loops, there doesn’t look to be too much danger that you could cut your finger on them. But there aren’t many more cells than usual in this glomerulus. It’s not an inflammatory appearance at all. It could be one of maybe two or three conditions until you look at the immunofluorescence.

Here we’re seeing IgG, immunoglobulin G. This is bound to the patient’s glomerular capillaries in this lumpy-bumpy, granular pattern that is typical of membranous nephropathy. You’re seeing autoantibodies binding to an antigen on the surface of the podocyte. The podocyte responds to this injury initially by producing more normal GBM material, membranous, thick glomerular basement membranes. As subsequently the glomerulus gets sicker, extra matrix is deposited in the mesangium, eventually the whole glomerulus can become sclerotic.

This is quite a common cause of nephrotic syndrome in adults – any of the 5 conditions we’ve highlighted can occur in adults. The disease is usually idiopathic, but there are a number of circumstances in which the cause is known. So for instance, a common cause used to be in reaction to gold therapy, which was used for rheumatoid arthritis. Mercury can do this, absorbed from skin lightening creams known to be sold in Asia and the Gulf, and a few other drugs have been identified as doing this. It can occur as a part of some other autoimmune systemic conditions, particularly lupus, but also rheumatoid and others. And in some circumstances it seems to be associated with cancer, but maybe not as often as once thought.

The antigens targeted are becoming known (interesting that it can be any of several). But at the moment, knowing which doesn’t make a big difference to how you treat it. The outcome of the idiopathic variety is typically given as

• about a third get better on their own
• about a third continue to have substantial proteinuria
• about a third deteriorate towards end stage renal disease, usually across a period of several years.

Now that may be modifiable by treatment. Initially to maximize kidney protection, with ACE inhibitors and blood pressure treatment. A statin will usually be a very relevant therapy in these patients with long standing heavy proteinuria.

But it’s an auto antibody mediated disease, so there are specific therapies you can apply to that. Particularly perhaps if you’re able to measure the auto antibody levels. The first successful treatment was to use an alkylating agent. So chemotherapy with cyclophosphamide or more recently anti-B cell antibodies like rituximab. The antibodies are slower and possibly not quite as effective, but both work.

Non-specific treatments to reduce proteinuria

If you can’t follow that route, then there are some non-specific interventions which do seem to be able to suppress proteinuria quite effectively pretty much regardless of cause. The immunosuppressive calcineurin inhibitors, tacrolimus and ciclosporin are particularly effective at doing that.You can apply these, plus ACE inhibitors, to any out-of-control nephrotic syndrome, if the side effects (including long term nephrotoxicity of calcineurin inhibitors) are acceptable.

That’s nephrosis

So that’s this cluster of diseases. Switched off podocytes, dead podocytes, Autoimmunity to podocytes, and the two systemic conditions discussed elsewhere.

Remember that can also occur with scar tissue deposition from inflammatory or destructive glomerulonephritis, which is the subject of the next segment.

• Back to parent page, Proteinuric diseases and nephrotic syndrome
• More like this – medcal.mvm.ed.ac.uk – Renal