Sunday, January 18, 2009

Rheumatoid arthritis and kidney stones

I just wanted to tidy up some loose ends I have in my head about rheumatoid arthritis, diet, kidney infections and kidney stones before I can get on to other ideas. Squiggs is over chickenpox and multiple on-call shifts are over for a while, so I just might get some blogging done...

My understanding of RA is based around Prof Ebringer's work, summarised here, linking urinary proteus infection to antibody production against its urease enzyme. The antibody against this bacterial protein cross reacts with the collagen in small joints and the end result is RA.

Why is RA so intractable? Why doesn't a short course of antibiotics clear up both the urinary proteus and the RA? There are several reasons.

As you well know, RA patients have a high incidence of kidney stones.

This is probably important and here's why:

Ammonia is pretty toxic to mammals, sufficiently toxic that we expend energy in joining two molecules of ammonia to one of carbon dioxide to give a relatively non toxic compound, urea. We can then excrete this with ease. Of course to a bacterium, with no concerns about the toxicity of ammonia to mammals, urea is just a food source. Splitting urea with a urease releases both the energy invested by the mammal and, unfortunately, the rather unpleasant ammonia.

What happens to the ammonmia? OK, it gets urinated out. But it also does two things on the way. First it renders the urine alkaline and second it provides NH4+ ions. So what? Both things are bad, but can be made worse.

There is also an association between RA and metabolic syndrome. Two of the hallmarks of metabolic syndrome are hyperglycaemia and hyperinsulinaemia. Importantly it is also associated with magnesium deficiency.

Because modern diets tend to be grossly magnesium deficient, you would expect the body to hang on to its magnesium as tightly as possible. But that doesn't seem to happen. Both hyperinsulinaemia and hyperglycaemia cause urinary magnesium loss.

So magnesuria in the face of magnesium deficiency is a feature of metabolic syndrome. What about a link between phosphate loss and insulin resistance? Metabolic syndrome is associated with phosphate loss in the urine too.

BTW: Coupled with the urinary calcium loss which also occurs, this is how you urinate your bones down the loo to get osteoporosis if you follow mainstream nutritional advice.


What do you get when you mix ammonium ions, magnesium ions and phosphate ions at an alkaline pH? Answer: Struvite urinary stones. Magnesium ammonium phosphate.

Struvite is a common form of urinary tract stone. It forms with ease when a person with metabolic syndrome (magnesium and phosphate in the urine) gets a low grade urinary infection with a urease producing bacterium (providing ammonium ions and an alkaline pH in the urine). Struvite is porous and harbours those very same urea splitting bacteria in a location where it is remarkably difficult to get antibiotics to penetrate... These stones can become enormous. They don't go away unless you sort out the metabolic syndrome as well as the urinary infection, which is often sub clinical and the person carrying it doesn't even know they have it. In fact the first warning sign many people with a kidney stone get is the sudden agony when the stone enters and stretches a ureter...

Proteus is one of the best struvite generating bacteria available. It's a normal commensal in the gut where it does well in the anaerobic conditions of the colon. It is highly motile and gets from the gut to the urinary tract with some ease. Ascending infection would be expected to be commoner in females than in males, owing to anatomical considerations. So RA should be commoner in females than males. It is.

So to summarise: A combination of metabolic syndrome with Proteus mirabilis infection is a generator of struvite stones. The bacterial enzyme used to extract energy from urea while generating ammonium ions has a peptide sequence remarkably similar to the collagen in small joints and is the best candidate to trigger rheumatoid arthritis. The process of urea splitting to release energy is an anaerobic reaction, the bacterium is just extracting the energy previously used to make the ammonia safe... Urea splitting is obviously well suited to the urinary tract, which is as anaerobic as the colon.

So antibiotic therapy tends to be limited in effect as it is difficult to clear the urinary infection in the presence of struvite stone(s) and difficult to dissolve the stones in the presence of metabolic syndrome. It is also essentially impossible to eliminate all proteus from the gut using antibiotics, provided the gut environment is convivial to the microbe. How does all of this fit in with diet?

I want to flick through the diet trials which have been used and those which haven't but perhaps should be. First thing to note is that, as detailed by Kjeldsen-Kragh, these trials are appallingly difficult to conduct.

Skoldstam's group started it all off back in the 1970s and looked at both fasting and vegetarianism. The fasting had some effect but there was always that niggly problem of only being able to use it for short periods and the vegetarian diet immediately re established the problem. They seem to have gone the vegetarian route as there was huge popular confidence in this approach at the time. It didn't work.

Another swedish group did that vegan diet diet study which was initially gluten free and found some effect, but only in the subgroup who adhered well to the diet (lapsing from the diet shows as the production of anti gliadin antibodies, only those who stayed anti gliadin antibody negative improved). You can't say from this study if it was the successful gluten avoidance which worked or the vegan aspect. But I can guess! They didn't look at proteus.

Kjeldsen-Kragh's group in Norway used a similar vegan gluten free diet followed by a vegetarian diet with some success. They were associated with Ebringer's proteus group from King's College. Here it was the subgroup which lowered both faecal proteus count and blood anti proteus IgG count which improved. They didn't look at anti gliadin antibodies but the initial diet was gluten free.

Skoldstam's group has more recently tried applying the Mediterranean Diet, at least as Mediterranian as envisaged in the Lyon heart study diet, based around canola oil gloop. Again they got some improvement, possibly due to improved lipid composition of the diet (more omega threes) rather than changing the disease process itself. I doesn't look like remission to me.


So how do you integrate all of this in to one concept? My feeling is that people will have to have a genetic predisposition. This will relate to those human leucocyte antigens known to be associated with RA (there are several). No one can change these and they simply set limits on what you can "get away with" in terms of your internal environment. These leucocyte antigens determine what you see as self or non-self. I don't see them as the "cause" per se. In general I feel genetics is phenomenally important in determining how we "break" under adverse conditions. Your genetics don't do the breaking. Mostly your diet does the breaking. Another post there to clarify that.

They have to have metabolic syndrome. This is side step-able.

They have to have intestinal dysbiosis with a predominance of proteus in their colonic bacteria. The best way to get this is probably to eat gluten but clearly gluten is not the be all and end all of the problem.

They have to have recurrent or continuous low grade urinary tract proteus infection, probably without signs and probably derived from their colonic bacterial population.

There may well be background maintenance of the immune response to proteus due to its ability to cross in to the blood stream directly from the gut and so be seen by the immune system, without necessarily invading the urinary tract. I think it is unlikely to be around and expressing urease for very long in the systemic circulation.

So that sums up the diets and the problems to me. It looks like you need to side step the metabolic syndrome while damping down proteus levels.

So which diet is out there in the mainstream and just crying out to be tried in RA?

Let's go back to Ray Audette and Neanderthin (bit of a collector's item by the current used prices!). This little book was not in my early reading but I've had a copy for some time. It's an interesting read, especially the early sections. Here Audette describes the miseries of his life with RA, which were later compounded by the additional miseries of type two diabetes. He did the paleo thing for his diabetes and virtually immediately ate his way to normoglycaemia. The RA went the same way as the diabetes.

Anyone reading Stephan's blog on diabetes trials will remember Lindeberg's paleo diet trial for human type two diabetes. Essentially, Lindeberg replicated Audette's approach in a bigger group than n=1. It was certainly quite effective for type two diabetes, despite not being a particularly LC approach. I suspect that reducing fruit consumption would improve Lindeberg's diet a lot, but it's pretty good as it is.

So what I would love to see is Lindeberg's diet applied to RA.

Okay, I'd really rather see the Optimal Diet applied to RA, but I'm not waiting around for that one...

Peter

24 comments:

Lee said...

Excellent post, Peter. Do you think vitamins D & K have a role worth mentioning?

I have had intermittant arthritic-like pains in my left ankle for almost 20 years, Shortly after starting OD, I supplemented with cod liver oil (15ml/day) and then vitamin D (usually 5000iu) with an occasional teaspoon of COL. I think that both supplements did me no favours, causing back pain, weakness and no ankle improvement. Now, adding vitamin K2 (1mg/day), I feel much stronger and the ankle pain has gone, although it is early days and could recurr. I think my dairy tolerance is better too. I am concerned though that such high dose supplementation could knock something else out of kilter.

JMC said...

Great post Peter. I was told by a friend that Loren Cordain tried to do a dietary intervention in the late 90s with a lectin, dairy and gluten free diet and without the foods that could lead to leaky gut. But unfortunately, he didn't get the grant.

Neverheless, he published a paper on RA in 2000, which was the basis of my dietary program (along with high omega 3 and vitamin D) with good results.

http://www.thepaleodiet.com/articles/Arthritis%20PDF.pdf

Recently, he wrote two articles on how tomatoes and egg whites could also be involved in auto-immunity and I have to say that after removing these foods (and stickng to the grain, legume and dairy free diet + Omega 3 + Vitamin D), I don't have any symptoms.


JMC

Chris said...

Wow. I think I'll put my copy of Neanderthin on ebay!

Christie said...

Hi Peter (and all of you other smart, well-read people),

My husband is HLA-b27 positive. We found this out 20 months ago when he had his first bout of uveitis. He is currently seeing an immunologist who has him on Humira (started with syringe shots, then she downgraded his need for it to just 2 pen shots every other week). His immunologist thinks that SOMEDAY his autoimmune disease will manifest itself as AS, but he has yet to show any symptoms of that. His only problem has been the uveitis, which he has had in both eyes at least 2 more times since the initial inflammation.

We are very worried about his vision as his prescription on his glasses for myopia has doubled in less than two years. All these ophthalmologists and his immunologist say about that is "that's likely to happen with such severe inflammations..." ! (I feel like all they're leaving out when they say that is "get used to the idea of going blind."!!)

I've found literally hundreds of testimonials from people with autoimmune disorders on the internet saying that once they changed their diet their symptoms greatly eased up or disappeared altogether, and if they have a flare-up, they can directly trace it back to some food they ate. Despite that, all his immunologist says about diet in relation to his autoimmune response is "I don't think it's going to do much for you, but feel free to try a diet change if you want." Of course, when I tell my husband about this blog and all it has to say about diet being directly linked to autoimmune diseases (not to mention the scores of people on the KickAS site who say similar things), he just quotes his immunologist and says he trusts her over some people on the internet he'll never meet.

It is killing me to watch this typical American doctor response (push the dangerous drugs, don't even ATTEMPT the safer, saner approach of looking for root causes and working your way up from there). Does any doctor out there at least TRY to treat the cause and not just the symptoms anymore?

What is left for us to do if these doctors don't even suggest that there are alternatives to heavy drugs (that clearly DON'T WORK, or the flare-ups wouldn't be happening every couple months)? Do they expect us to just let my husband's eyesight slowly fail because "that's bound to happen" with this illness? I read on the KickAS forum that seeing an ocular immunologist would be a good idea if you suffer from iritis/uveitis, but they are hard to come by. And even if I do find one, will they just prescribe the same treatment as his immunologist?

Has anyone out there been able to get their spouse to radically change their diet despite their doctor's advice/treatment? My husband's not likely to give up something as mainstream as bread and starches if his doctor doesn't practically demand it and tell him point blank that his eyesight depends on it.

Sorry for the lengthy post.

Despairingly,
C.B.

Peter said...

Hi Christie,

Sorry to hear the story, but I think it's quite common. Apart from the fairly draconian changes to diet needed for an HLA-B27 positive person with uveitis to make, you are also stuck with the fact that there are months between episodes and lapsing occasionally, without consequences, would seriously undermine anyone's resolve.

The flips side is that, for some HLA-B27 positive people, even miniscule amounts of starch will trigger a flare and people might go low starch when they need to be no starch and just consider it not worth continuing. There does seem to be a wide variation from what I've read.

Even simple things like some D3 may not meet with medical approval, though it's very easy to do, so might meet less resistance. More complex things like normalising your fatty acid balance needs more than fish oil. Going minimal omega 6 in the USA is about as wrenching as zero starch.

In many ways you would get on better if your husband had a clear cut marker like gut pain to demonstrate, promptly, that he was on to something. No such luck..........

I think I'm taking rather a long time to say I think you are in a very difficult and un enviable position. The couples I know who have done this have been shared in their approach. Occasionally one half has gone LC by being self motivated, then the other half has seen the results and followed. With a monogenetic problem HLA-B27 specific uveitis you're not going to lead the way by example...

I can sympathise with you, but I don't think there is much anyone can do to help.

Oh, almost forgot. Presenting your case is fine, being supportive is crucial, too much persistence will be counter productive. He's going to need your support. Being there seems very important whatever route he takes.

Peter

BTW, if anyone else has any more positive thoughts or experiences than me, please SHOUT!

Peter said...

Hi JMC,

Yes Cordain's diet does seem similar to Lindeberg's (glad it has helped). Not surprising as they have been co authors on some of the Kitava papers. As Miguel commented on another thread, Cordain seems to be a nice guy. I just can't cope with his cholesterophobia. Eades likes him and they agree to differ on cholesterol and saturated fats, from what I gather on his (Eades') blog. But for a saturophile with and LDL too high to even think of statinating it down to 70mg/dl.....

Peter

Christie said...

Thank you so much for your consideration of my dilemma! You are absolutely right - what makes any diet change pretty much an impossible sell is the fact that so much time goes between uveitis occurrences that my husband most likely WOULD lose interest in trying. Or, he wouldn't be vigilant enough about it and then blame the diet when he has a flare-up instead of looking into WHY it might not have worked.

Thanks again for your input, and to anyone else with advice/information. I really appreciate your blog, Peter. I feel so lucky that all this valuable information is FREE!

JMC said...

Thanks Peter.

I seem to agree with you regarding cholesterol and LDL, but from the stuff I've read from Cordain (not his book, but his old articles and all his papers), his theory is basically this: if H/G living in their natural environment have certain biochemical indicators, then that should be considered normal, and I believe that is what he tried to say in the LDL papers (where he only wrote the evolutionary part, as Miguel said).

A good friend of mine colaborates with Cordain and he told me that he is a really nice guy, very professional and very open to debate ideas. He also told me that he doesn't recommend or takes statins and that he doesn't consider saturated fat to be a major player in atherosclerosis, although he doesn't totally dismiss it (simply because 12:0, 14:0 & 16:0 elevate LDL).

Here's an interview between Cordain and Feinman that I enjoyed:

http://lavida.kgnu.net/lavidaradioshow.php?show_id=331

See also his newsletter article on lectins and atherosclerosis:

http://www.deflame.com/Portals/0/Wheat%20lectins,%20heart%20disease,%202008.pdf

My friend tells me that Eades is a good friend of Cordain (they were co-authors in a paper) and they subscribe frequently.

Also, I've read an article on egg whites and auto-immunity that he is selling as part of an MS dietary program and in it he states that eggs improve lipid profile and that dietary cholesterol is not an enemy.

You know, I think Cordain is a very bright guy and good person doing research no else wants to do (and being criticized because of it), but as every human being, he makes mistakes and doesn't have all the answers. But his program has helped me a lot.

Regarding you Peter, I think you're a kind of biochemist and physiology genious (I'm a biomedical sciences finalist and I would love to pursue my studies in immunology, but by reading your posts, I realize I still have a lot to study to master Biochemistry and Physiology as you do). Moreover, in my opinion, your blog is the best one on the web regarding Nutrition.

As so, I would really like to see you join forces with Cordain, since you two are rare individuals who have sane ideas about diet & auto-immunity (my rheumatologist dismisses diet alltogether, other than saying that Omega 3 fatty acids may have a minor benefit, which isn't true, based on the scientific literature I've read).

Sorry for this very long post.

JMC

Peter said...

That seems to be the geneal impression I'm getting from quite a few sources. Maybe I shouldn't be so grouchy!

Peter

BTW the egg white comment is very interesting. Just on the basis of logic, the white should be designed to keep bacteria (and discourage mammalian predation) away from the yolk, so there is scope for lots of tweaks of protein function here that might not be too kind to a mammal eating them. Obviously birds don't like carnivores any more than plants like herbivores, and the egg can only do chemical warfare, plant style...

Arctic said...

I was wondering what the deal with yolk only was. I thought that it had something to do with the limited protein intake of your diet... I still eat em' whole. Seems like a waste to throw anything edible away.

Im by no means an expert, if even a novice, in these matters but I would presume that eggs have been eaten relatively whole during the human history. Is the egg white anti-bacterial?

marco said...

Sorry Peter,
could you have RA without Proteus as well as AS without Klebsiella?

JMC said...

Thanks Peter.

Artic,

If you have specific HLA haplotypes that predispose you to auto-immunity (like I do), then egg whites (as well as saponins, lectins, gluten, some dairy proteins) may adversly afect you.

Otherwise, I think egg whites are probably ok, but I could be flat wrong.

JMC

Peter said...

Marco, yes, and going to a LC paleo diet would probably work for most. There are a whole range of HLAs which look at a whole range of bacterial and dietary peptides. There are even sub groups of HLA-B27, some of which are associated with disease, others not. If any of them can also "see" your collagen, once set up by the exogenous trigger, you are set up for a rheumatoid /AS like disease. Biology is never hard and fast. Ebringer brings us the basic principles and a group of examples. MS is the next set of posts along these lines. But evolution is random and keeps many options open, some good, some bad. We then push the limits and see how we evolve/break. If this features RA or AS that's tough, we should un-evolve a bit and go back to our roots, then see what happens...

peter

Peter said...

Arctic, re albumin, apprently so but the papers are all old, not in English, and have no abstracts on pubmed, just titles!

Peter

But eggs come out of a chicken's bottom, so need to defend themselves against germs rather well...

Peter said...

Lee, never answered re D and K. Probably matter, ditto PUFA amounts and ratios. I asked Prof E about these aspects and he feels they probably do matter. He's an immunologist, so does look at these things from his perspective, as we all do.

Peter

Tim TerlegÄrd said...

This seems like logic reasoning for an amateur like me.

I also read that smoking is a common cause for RA. What is the mechanism leading to RA there? I have a friend with RA and she does not have metabolic syndrome (atleast it doesn't look like it, she's slim). Are the mechanisms a bit different for smokers getting RA?

Peter said...

Hi Tim,

I'd be very carefull about deciding who has metabolic syndrome and who hasn't, if your diet is carb based and you are normoglycaemic, you might still need to be hyperinsulinaemic to achieve this, so be magnesuric...

Smoking (complete guess) might amplify the inflamatory response mediated by pro inflammatory cytokines generated either from the immune attack or resulting from insulin resistance. Just a guess. If so, you would expect it to be associated with other AI diseases but I've not checked this. As mentioned to Marco, there could easily be other small joint arthritides related to othe HLAs and other peptides. RA is a description of the impact site, rather than telling you exactly which brand of artilery shell hit the joints...

Peter

Chris said...

Re Smoking - there is a link with other autoimmune diseases. I have a (girl)friend who is an immunologist working in a group that is looking at the impact of smoking on Crohn's disease and Ulcerative colitis. I can't remember which way round it is but it makes one of the diseases worse and seems to protect you from the other. As usual there is a load of genetic stuff that everyone is looking at now connected with this.

Peter said...

Hi Chris,

Yes, I remember you saying. I've googled this subject and it seems like many auto immune problems are worsened by smoking, probably a non specific effect up regulating the immune system in response to chronic damage....

Peter

Chris said...

..... although - typically - when I was chatting to her about this at the weekend she was telling me her theory that IBD is not autoimmune more about your body reacting badly to gut flora. She thinks there is a lot to the hygeine hypothesis. When our environment is full antibacterial soaps etc your immune system has less to work on and so starts attacking things it shouldn't .....

Dr. B G said...

Interesting thread here!!

I've asked Robb Wolf about Cordain -- Robb eats a lotta sat fats...(lard, coconut oil, beef -- no dairy, no peaunuts, no legumes) and advises of course for Crossfit as well, as you know.

Cordain must be pretty cool (like Peter *smile)...the too differ on these minor but significant points.

From what I read about eicosanoids, hormone cascades and imbalances, I do see the point that Cordain may be trying to make. When we are ill and the inflammatory status particularly high (ie weighted toward omega-6, naturally endogenously v. omega-3/less COX LOX etc/E3 v. E1/etc) then consumption of high saturated fatty acids may exacerbate the situation. Why? High fat meat, organ meats and dairy have more arachidonic acid, an omega-6 with pro-inflammatory effects with the enzymes to convert it to other eicasonoids are not working properly. Many cancer protocols probably adhere to low AA content meal plans for this reason, I suspect.

For healthy, balanced individuals however there should be no issue what so ever with sat fats.

Great discussion!

-G

Peter said...

Yes Chris, I'm a hygiene hypothesis believer, in a "not really read up about it" sort of way, too. Certainly if Squiggs wants to eat soil in the vegetable garden, I'm not up in arms to wash his mouth out with bacteriacidal mouth wash. A few germs seems like a good idea to me. I don't see that many HGs looking to wash their hands every two minutes. The main use of the germ theory of disease seems to be to sell disinfectant...

Re the GI tract, the more I read through the huge stack of papers I got from prof Ebringer, the more reasonable it seems to me that very few auto immune diseases are truly auto immune. Most probably use a bacterial or food component as the primer for the immune system to attack, which catches "self" in the crossfire. As 80% of the immune system is in the gut it's not so surprising that severe inflammatory GI probs result when an unacceptable mix of bugs is there, fed by a crap diet....

BTW that endotoxin/fat meal paper you sent me is great. I've got a follow on paper which goes some way to explain why this isn't as big a problem as you would think... Just need the time!

G, yes, it strikes me as similar to Ron Rosedale's preference for monounsaturates over saturates in seriously damaged people. We all get our own slants. As Miguel and JMC have pointed out, Cordain supplied the paleo aspects, not the LDL-is-poison aspects to the papers on his web site. But that's a hell of a burden to carry, having your name on those papers, when people look at the cholesterol hypothesis with any sort of critical approach. Still, I think I'm being convinced to relax about this...

Actually it makes me think of Dr D's latest post on acute lipid deterioration after Christmas in a 60 60 60er. All this clever detective work on lipids to tell that there had been a glycaemic lapse over the holidays. A simple fructosamine would have told him this without all the searching through the down stream effects on lipids. But people who work to the lipid hypothesis can still do good stuff!

Peter

Stan (Heretic) said...

On the topic of autoimmune diseases, here is a very interesting spin on it:

"Are worms vital to human health?"

M said...

Hi! I've been reading your blog with great interest, thank you for all this great information. I have all sorts of inflammatory conditions so I've searched for an appropriate diet and am now of course following a very LC, high fat diet (again, thank you). One thing you might find interesting is that one of my first approaches was to take lots of fiber, in the form of wheat bran (seeing as it has 45 gr of fiber per 100 grams). Someone like Dr. Robert Lustig says we don't know how high the fiber intake has to be until it's toxic, because no one can eat that much fiber, that it's harmless and the more the merrier. But for what it's worth my personal experience was that at first it seemed to work fine and then I had to stop due to very bad pain in the kidneys and feeling generally so bad I didn't know if I was going to throw up or pass out or what. I'll never put another spoonfull of bran in my mouth ever again, that's how bad it was. So yes, it's toxic.

On an unrelated note, I've read somewhere that when you're on antibiotics you should stop taking probiotics, because these render the antibiotics useless. Is this true? If so, do you think it's possible that regularly taking probiotics would render meat from animals that have been raised on antibiotics safer to eat?