Focal segmental glomerulosclerosis

Published on August 31, 2016   38 min

Other Talks in the Series: The Kidney in Health and Disease

0:00
Hello. My name is Moin Saleem, I'm the Professor of Paediatric Renal Medicine at the University of Bristol in the UK and the Children's Renal Unit. I'm gonna talk today about focal segmental glomerulosclerosis.
0:13
So first to put this into context; this is about the kidney's filter. The kidney, I call the world's most sophisticated filter. And the filtration unit of the kidney is the glomerulus. The glomerulus is a specialized capillary bed. And we have about a million to two million of these each.
0:34
And when the glomerulus breaks down and the filtration breaks down, we get what is called, the idiopathic nephrotic syndrome. And this results in heavy proteinuria, so protein leaks from the bloodstream into the urine, low-levels of protein in the blood particularly happens. And so you get hypoalbuminaemia which leads to low osmotic pressures in the inter-vascular space. And which leads to peripheral tissue oedema, which you can see here. Rugby player Jonah Lomu, is a very famous patient with nephrotic syndrome, who sadly died.
1:05
I'm a pediatric nephrologist and I see mainly children, so clinically in children the size of oedema are in the lower limbs, you can see it here. The abdomen where you get ascites. And facial oedema, as you can see here.
1:19
So idiopathic nephrotic syndrome has various different classifications and are usually based on observational signs. It can be classified histologically; so it can be classified as minimal change nephrotic syndrome or as focal segmental glomerulosclerosis. I'll expand on that in a bit. It can also be classified by steroid response. So you can have steroid sensitive nephrotic syndrome, or steroid resistant nephrotic syndrome and various different nuances of those different responses. Both of these classifications have overlaps and they're not based on the mechanism of the underlying disease.
1:56
Minimal change nephrotic syndrome is so-called because when you do light microscopy, on the histology you see absolutely no change in the glomerulus, it looks completely normal. And also immunologically there are no immune deposits and no other signs of immune activation. So this is a disease that cannot be detected by light microscopy in terms of pathology.
2:18
In focal segmental glomerulosclerosis, on the other hand, which tends to be a more severe form of the disease; and also has an alternative terminology of steroid resistant nephrotic syndrome; what you see is areas of sclerosis and fibrosis, so scarring within the glomerulus, in segments of the glomerulus. And this is the classic form of this disease histologically.
2:42
The steroid-based classification is again slightly different but it's based on steroid resistance or steroid sensitivity. And the steroid resistant groups can be either primary steroid resistant where there is resistance from the outset clinically and the patient never responds to any steroids. Or secondary steroid resistance which can go through various phases of being either infrequent relapsers, frequent relapsers, etc... until that patient will become resistant in certain cases. And then, we have a category of presumed steroid resistance where these may be very early onset familial or genetic cases most usually. The steroid resistant cases are probably a mixture of genetic disease and also, what I call, circulating factor disease, which I'll expand on as we go through. The steroid sensitive cases are much more likely to be circulating factor disease. And I said, some steroid sensitive patients can become steroid resistant, but a very small proportion of any of these patients will have a genetic disease underlying their condition.
3:46
So this is a disease of the filtration barrier, with still lots of conundrums that we don't understand. Is it an immune disease? What we know is that viral triggers and can result in relapses and that certain patients respond to steroids or other immunosuppression. But in the kidney, in the glomerulus there are often no immune infiltrates to suggest an intrinsic immune deposition or abnormality. And therefore it's been hypothesized for decades now, that a circulating factor is likely to cause at least a subset of this type of disease. Are there non-immune versions of the disease? While certainly some patients never respond to immunosuppression, there can be occurrence in families and they can occur with extra renal features suggestive of syndromes. So the challenge is to understand the disease mechanism underlying the clinical, and the molecular observations that we're making. And the advances in biology of the glomerular filtration barrier that have been made in the last 10 to 15 years. And then to stratify our patients better using these mechanistic insights.
4:49
So our current clinical classification, I think is unsafe. And mechanistically, we need to know whether these are the same with different diseases and how different they might be. And the way to approach this is to look initially at the final common target, which is the glomerular podocyte.
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Focal segmental glomerulosclerosis

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