CME Slides Forum - M.R. Francis

A joint Congress by ERA-EDTA and ISN

TROPICAL INFECTIONS AND GLOMERULONEPHRITIS

Magdy R. Francis, Cairo, Egypt

Chair: Charles Alpers, Seattle, USA

Kerstin Amann, Erlangen, Germany

kasr el aini

Dr. M.R. Francis
Pathology Department
Kasr El Aini Faculty of Medicine
Cairo, Egypt

Thank you Chairpersons. Thank you for inviting me, thank you to those who suggested it.
I took the liberty of putting side to side Leonardo da Vinci and Imhotep because although there are some 5500 years between them they are very similar being architects and scientists and a lot of things.

Now in the next few minutes I will try to touch these points: why this subject in particular? Is this just because exotic is nice? Does it have an epidemiological and geopolitical importance? Very rapidly a classification. A hint on mechanisms, one or two examples and a carry-out message about further things to be done.

Of course, they are fascinating just the names remember your medical studies the Loa loa, the plasmodium, the elephantiasis, the Verruca peruana, the lovely Dracucnculus medinensis, Capillaria philippinensis, the japonicum all very nice names but it’s not only a nice thing it’s because it’s affecting patients in quite a broad area between the tropic of Cancer and the tropic of Capricorn.

Now some would argue that I come from Cairo and so I’m not from this area at all, I’m just outside but we are not very geographically correct we extend it to the subtropical areas or clearly to all those areas that have this variety of weathers ranging from very humid tropical areas to subtropical, aired, to very aired regions.

Not only it’s a big part of the world but it’s a big part of the population because in this modified map you can see that a big part of the world is actually in this region

A dramatic map is the following map which is the public health spending per capita in these regions.

Now I’m not going to turn this into a geopolitical thing but it explains to you why we don’t very often have very accurate statistics about the prevalence of tropical infections and the prevalence of glomerulonephritis related to these tropical infections. It’s just by extrapolation from what we know of the importance of disease that we know what is the possible prevalence and magnitude of the problem.

We have to know that the presence of these tropical infections may influence the pathological presentations of the glomerulopathies in general in the region. There will be more membranoproliferative reaction for instance, some areas will have more focal segmental sclerosis, glomerulosclerosis. There are areas of the world where there will be more IgA deposition etc. They were restricted to tropical regions before but now of course, with the ease of travel you will encounter them more and more in temperate climates.

If we take plasmodium as an example, in the last part of the last century it was stated very clearly in text books of pathology that if minimal change were the commonest cause of nephrotic syndrome in children in the temperate areas, if you take the whole world as a whole, it would be malarial nephropathy which would be the most important cause. Of course this has been challenged by many, many people but still it remains quite an important cause because if according to the WHO you have some 250 million, we had 250 million cases in 2006, some of them with co-infection, with HIV especially in Africa and if we know that in some parts of the world there is a very high proportion of cases with malarial nephropathy and if we know also that in the areas where malaria has been eradicated there has been a very important decrease in glomerulopathy, then we know that there is quite a strong relation between them.

Of course, it’s not always easy to prove a cause to effect relationship because we rely either on epidemiological or statistical data and sometimes we don’t have enough data to do that and sometimes they are fallacious because the disease is too rare or too prevalent, everybody has the tropical infection and we had this problem in Egypt at the time when everybody had schistosomiasis, so of course, it was very difficult to prove the relation between schistosomiasis and different pathologies and also you can have coexistent infections, schistosomiasis and HCV schistosomiasis and salmonella as we’re going to see.
Histologically and immunologically it’s not always although in theory it’s nice to co-localise antigens it’s quite hard to do it in clinical practice because they’re not always available clinically or commercially and it’s not even a 100% proof neither the absence 100% negative proof.

This is from a paper we did Professor Barsoum and myself a few years ago on several thousands of biopsies and these were the results of the patients who were on ESRD in Egypt which is already subtropical and you see that there are quite a good number which are related to diseases which can be related to infections for proliferative nephritis, amyloidosis and that a good proportion of end stage kidneys are still present and we don’t know if they’re not related to infections.

We did the same about the patients with nephrotic syndrome or subnephrotic proteinuria and you can see that we have a very high proportion of FSGS and also quite an important proportion of the proliferative glomerulonephritides and quite a reasonably important proportion of amyloid.

Of course, the ‘classical’ archetypes of pathological mechanisms are present in tropical infective glomerulopathies but sometimes the presence of the tropical infections especially if it is parasitic will add a certain spice to the story and additional mechanisms, not uncommonly you have a combination between one or two mechanisms due to one or two organisms.

A question very often asked is what would you call a tropical infection? This was the title of the lecture and you can ask yourself what can be tropical and what cannot be tropical? Of course there are those who are restricted to tropical areas because the parasite or the organisms do not live outside the tropical areas but there are also those infections which have been controlled in other areas of the world and which tend to be more severe in the tropics because comorbidities, lack of treatments because the environment or the racial characteristics are favouring it. Remember leprosy, for instance, leprosy now you could consider it as a tropical infection although in the middle ages it was a universal infection.

Now I’m not going to go through all of them, I don’t want you to kill me but I’m just going to show you that the spectrum is quite wide. Of course, this is not a comprehensive list, we have taken the example of salmonella, shigella, leptospira, -- tuberculosis and I’m stressing on the methicillin-resistant staphylococcal A infection because this is emerging in many reports and we have seen it and anyhow this is just to show you that you can have wide scope of pathologies in one type of infection. For instance, in this case you can have from crescentic glomerulonephritis to necrotising glomerulonephritis to just some proliferation or exudative GN.
In the case of salmonella we have found that when it is associated with schistosomiasis, you have a quite important exudative glomerulonephritis response and we’re going to see it in schistosoma cases.

The same for viruses and we have heard about the collapsing glomerulopathy, collapsing FSGS. This is particularly in HIV but you can see the range of things HIV can do and also the same for HCV mainly with mesangial capillary glomerulonephritis, cryoglobulinemic or FSGS.

About the parasitic and protozoal maybe the one we are most accustomed with in Egypt is the Schistosoma mansoni infection and they also can present with a variety of patterns, especially if associated with liver cirrhosis or with liver fibrosis much less in Schistosoma japonicum and hematobium when there is mainly mesangial proliferation.
The Plasmodium falciparum is mainly associated with acute inflammations while the Plasmodium malariae is mainly associated with chronic immune depositions and mesangial capillary pattern of proliferation.

The broad lines of response are the same except that apart from the antigen here the macrophage has a very pivotal role. Because it’s going to stimulate the TH2 or TH1 lymphocytes and these are in turn going to stimulate the B cells which are going to produce immunoglobulins forming the circulating immune complex. At the same time there will be an interaction with xenophiles with the aim of killing the parasites. I took the liberty of taking the few following slides from Doctor Barsoum’s lecture on the thing I’m not going to enter into detail but just to show you that apart from the beauty of the slides, the beauty of the complexity of the possible mechanisms acting on the different parts of the glomerulus.

So these are the broad lines with early cytokines and later on later cytokines changing the naïve T lymphocytes into TH1 or TH2 but also at the same time there is an interaction with natural killer cells, with platelets with the liberation of several factors

and this can act directly on the endothelial cells either directly sub-binding to the Gb3 receptor or through several factors, as you can see from TNF-α to P3, angiotensin II, the --- cyclines, NO or through the circulating immune complex and the formation of the membrane attack complex.

This in turn is going to act on the mesangial cells and also through the regulation of several factors might end with mesangial matrix deposition or mesangial lysis.

We can also have crescentic response either through reactive oxygen species, interleukins or platelet derived factors.

Now the patterns we encounter unfortunately we don’t or we seldom have pathognomic patterns as anything in pathology in kidney disease and so you certain diseases are going to share certain different patterns. Mainly the proliferative glomerulonephritis which is a mesangial proliferation will be in the post-viral cases, in the post bacterial and in the post schistosoma whether mansoni or hematobium or japonicum.

The pauci-immune glomerulonephritis which we can find within focal necrotising glomerulonephritis is found mainly in Staph aureus infection or in HBV vasculitis.

The diffuse exudative glomerulonephritis is, of course, seen in the severe cases of post-streptococcal infection we encountered but also in salmonella infection especially if they are associated with Schistosoma mansoni. They can be also found in HIV and filariasis.

We encounter crescentic glomerulonephritis sometimes in streptococcal infection complicating scabies, in the MRSA and in the different pathologies which will cause cryoglobulinemia.

A pattern of mesangiocapillary GN is famous with hepatitis C, it can also be encountered in CMV, EBV and HIV. It is also famous in the cases of Schistosomiasis and Hydatid disease.

A word about the IgA or IgA deposition. It is described in HIV and other causes of viruses but it has an important role in Schistosomal glomerulopathy because it seems that it is related to the progression of the disease.

Focal segmental in the case of Schistosomiasis it is common in African children, so it has not been reported much in other parts especially with hepatosplenic schistosomiasis.

Membranous patterns are common in HBV, less common in HCV and we have a specific pattern of type III in quartan malaria sometimes in schistosomiasis and other infections.

Amyloid and this is the bi refringence of course, tuberculosis, schistosomiasis and leprosy remain very important causes in the tropics.

A word about Schistosomal glomerulopathy. It occurs with Schistosoma mansoni and you know that in Schistosoma mansoni you end up by depositing the eggs in the portal tract or even the worms which are in the portal circulation, they embolise in the liver, they cause a reaction which causes portal fibrosis which is usually not associated with a parenchymal affection or marked by parenchymal infection, it’s mainly a vascular thing a presinusoidal block. As a result of this you have opening of many of the collaterals like in any case of sclerosis but even more so and so quite a good shunting from the portal circulation to the systemic circulation.

Now this is a picture of the schistosoma ova and you can see there is a very severe reaction which can occur around the living ova. Once the ova are dead, then you don’t have this severe fibrinoid necrotising reaction around, other severe inflammatory reactions more peripherally and they just become calcified. Now the reverse occurs with the worm, when the worm is living, it elicits very little of the reaction. Now there is some inflammation here but there is not hopefully this phenomenon around. But they continue to discharge the antigens because these are living organisms and they are very tricky. They can escape the immune recognition of the host. I’ve put this picture of a scanning EM because it is very nice, a couple on honeymoon, the male and the female and a very long honeymoon and you can see the small irregularities on the cuticle and this is where sometimes the salmonella hides and in this case you will have a proliferative exudative reaction.

So this is the basic mechanism, the worms in the portal vein with later on granulomata in the portal tract, there will be liberation of antigen. There is switching of increased IgA production, impaired macrophage function which doesn’t clear this IgA, formation of immune complexes and glomerular deposits.

Accordingly the following patterns have been encountered in Schistosomal nephropathy. A mesangial proliferation usually with IgM deposition but it can also occur in hematobium and japonicum, it’s not always progressive. Sometimes an exudative type of GN, especially if you have salmonella with it. Very rarely crescentic GN occurs.
Now this transition zone between the proliferative and the mesangial capillaries and we like to call it in this case mesangial proliferation with focal mesangiocapillary changes, a very twilight zone I must say. FSGS and a separate entity but which has to be said here an increasing number of amyloid deposition.

These are the different examples, the mesangial proliferative a little bit more in the case of the early cases what was called class I with IgM deposition later on with IgA.

One case of segmental sclerosis and so-called class III with this mesangiocapillary type of proliferation sometimes complicated by HCV, so that you have a superimposed cryoglobulinemic reaction around it.

In the case of amyloid of course, you have two factors, the macrophage producing AA protein and at the same time there is interleukin 1 and 6 which make the hepatocytes unable to clear this AA protein so there is increased tissue deposition and amyloidosis occurred.

So the reaction in the case of Schistosomiasis can be modulated as you can see by many things. The state of the hepatic function, the portal hypertension, whether it’s important or not, the stage of the macrophage, is there or not salmonella infection? Is there or not HCV infection? Treatment, of course, cases of Schistosomal glomerulopathy are now fading away because there is an effective treatment with Praziquantil orally and it has drastically decreased although the proportion of cases with glomerulopathy to the proportion of cases with schistosomiasis hasn’t changed, it’s the same proportion.

Plasmodium malariae is mainly a membranoproliferative pattern with mesangial dense intramembranous and subendothelial deposits. It’s possible that there are genetic and environmental factors playing a role. It’s usually not reversible. The falciparum on the other hand is an immune complex-mediated exudative glomerulonephritis. It can be reversed by treatment, it is, of course, also associated commonly with acute tubular necrosis and it seems, according to the WHO, that the concomitant infection with HIV can play quite an aggravationg role.

We don’t see it much in Egypt, so this is a picture from the article by Van den Berg and Sandrine Florquin, they are even then quoting somebody from France and this is one of the rare cases we see in Egypt, they usually come from Sudan.

There are two different mechanisms, the mechanism of haemolysis and the concomitant mechanism of macrophage stimulation with immunoglobulin deposition leading at the end of the day to the glomerular pathology. This is the case of falciparum.

These are the small knobs which have been shown on the surface of the -- make them attached to the basement membrane and you can have a segmental necrotising response or a diffuse proliferative response.

Now Mr. Chairman, Chairpersons, can I give the following carry-out message that they are important epidemiologically, they are fascinating from a pathogenic point of view but they do surely deserve more clinico-pathological studies and it’s important to encourage registries and at least pathology services in the vast part of the world where it’s not sometimes available.

Don’t forget to see this beautiful painting in one of the Milano museums. It’s by Bruegel. Thank you.

Chairman: So this very stimulating presentation is available for discussion. Please?

Question: At the beginning of your lecture you mentioned MRSA as a cause of tropical glomerulopathy. I don’t whether it is tropical? This is the first question, number two what type of glomerulopathies does it cause because we deal with it sometimes in some patients and we’ve seen it a lot so I would like to know what are the long sequelae or what specific type of glomerulopathies does it cause, MRSA?

Dr. Francis: You have a quite a wide variety you can have just an exudative or a severe crescentic and I don’t know in your experience but in our experience it wasn’t present before in the tropical areas and now it starting to be more and more present. But it is a very wide range they are mainly crescentic. What type of glomerular pathology? Mainly crescentic, proliferative with crescents, these are the ones we see.

Chairman: Are there other questions? You’ve challenged the audience. --- places we’re not normally thinking. I think the questions may come later. Agnes?

Question: I wonder if any other of the lesions other than what you mentioned were just the schistosoma that might be able to respond. You said only some had been able to improve, are there any other diseases where you can give hope that this is a pattern that can get better with treatment of all of the examples you give, or is the ones that you mentioned I think particularly with falciparum and schistosoma that these could maybe sometimes improve or are the patients doomed to have progressive disease?

Dr. Francis: Well, Agnes the patient improved, I mean the cases decreased in case of schistosoma because the schistosoma was treated not because it was reversed.

Dr. Francis: Of course, falciparum once treated reverses, the other ones usually progress. Your only way to tackle this is to eradicate the disease.

Question: So in patients who have existing glomerulopathy that is linked to one of these infections it’s rare that they can improve if the infection is treated.

Question: I mean there are some cases of the secondary amyloid that have proved.

Dr. Francis: Yes the one from Sudan reported by Booth of course have shown decrease in amyloid but there were cases which originally had no interstitial fibrosis and you know that those do quite nicely anyhow. But apart from this I think that once you have reached the stage of mesangial capillary glomerulonephritis it is hard to think that it’s going to reverse.

Question: I have a second question if there’s time. In a large percent of your biopsies the morphologic change is one of chronic interstitial nephritis. What in your experience are some of the possible contributors to that broad category? Do you think they are related to chronic reaction, to infections, to drugs or herbs or do you have any experience or thoughts on that?

Dr. Francis: You are talking about the interstitial nephritis because we were talking about the glomerular disease.

Question: Yes, I realise that that’s why I realise the title of your talk but in your early slides you gave a series of the prevalence of diagnoses that you had in the biopsy and I wondered whether some of those chronic interstitial nephrites might also be infection-related.

Dr. Francis: It might but of course you’re dealing with a community as you know where any drug over the counter is allowed, this is one, where you have chronic infection because of course, schistosomiasis is going also to have as an example chronic infections and so it’s very hard to know which one is the most contributing. But a good amount of them would have some chronic infection in the kidneys too. Thank you.