I read a lot about “inflammation” in renal patients. Could you define “inflammation” ? What exactly is inflamed? How exactly does reduced renal function cause this inflammation? What exacerbates it? Is it more advanced in a stage 5 patient on dialysis than on a stage 3 or 4 patient not on dialysis? Does the dialysis process itself exacerbate it? Does optimal dialysis minimize it? How is it treated and/or prevented in a stage 4 patient? CAN it be prevented, or does it just come with the territory? Shall I think up more questions on this topic…? haha
Oh dear … where do I start! This is the most extensive question ever asked here so, to avoid writing a text book of nephrology – for that’s what this requires to answer it well - I will give overview answers which may not be enough but will have to do!
Could you define "inflammation … and what exactly is ‘inflamed’?
To paraphrase the introductory paragraph on inflammation from Wikipedia (always a good resource for definitions of common things) … inflammation (from the Latin “inflammare” = to set on fire) is part of the complex biological response of vascular tissues to any harmful stimulus. Remember the ‘vascular’ bit - we’ll come back to that!
Such ‘harmful’ stimuli may be ‘ a pathogen’ – commonly this might be a bacterium or a virus – or it might be a noxious or ‘tissue-toxic’ toxin … or it might be that other damaged adjacent or distant cells have leaked their potent mix of cellular enzymes (some irritative, some digestive) called ‘chemokines’, ‘cytokines’ or ‘lysosomal enzymes’ into the adjacent tissues. When this happens, a damaging ‘cascade’ can be set off in nearby cells and tissues. There is an almost endless array of cellular irritants – stuff that angers and stirs cells up to 'do war’ on nearby cells or on themselves.
Consider what might happen is someone lobbed a grenade into your local housing block. There would be some close major damage – even deaths, some more distant lesser damage – injuries, and a whole lot of angry residents pouring into the street(s) to retaliate, fight back, raise hell etc. People might just calmly assess the damage, repair the wounds, check that there is no more threat and settle down, after a bit of yelling and shouting. However – and sometimes – the situation might get out-of-control, and what should have been a locally-assessed, contained and settled dispute could then spill over more widely to adjacent blocks, even suburbs, as a general riot – or even through the whole city. In the extreme, it could even become a civil war.
Just think of some of the conflicts around the world – if only they had been contained early on, or locally … what a different better place our world would be.
Oddly, inflammation is actually - early on and if confined - a protective attempt to respond to and remove the injurious stimulus or stimuli and to initiate the healing process. This is the kind of measured, controlled response that would happen if common sense prevailed after the initial ‘grenade’ lobs and tempers were controlled. The damage would be contained and calm heads and hearts would win out. The initial ‘event’ would lead to the identification, isolation and capture of the rogue ‘lobber’, calm repair and restoration of normality would ensue, and things would return to normal … OK, a bit of grumbling for a while - but then calm.
Consider a ‘zit’ … a locally infected skin pore cause by some bacteria ‘trapped’ in the pore … which flares and is locally ‘battled’. The killed bacteria are then ejected in a squirt of pus while the surrounding locally angry tissue and cells - after a flush of red anger - settle down and return to their normal state. In this example, the threat has been contained and eliminated and little or no permanent harm is done.
But … sometimes inflammatory warfare can spread more widely, affecting multiple tissues and organs – in our analogy, a civil war … or even a ‘world’ war.
So, too, it is with inflammation – it can be contained or generalised.
But …remember … inflammation is the response, not the stimulus itself. Nor is ‘inflammation’ a synonym for ‘infection’ – the infection is the stimulus that triggers the inflammatory response, not the response itself. The response is what is called inflammation … or, as doctors call it, the ‘inflammatory response’!
In humans, the inflammatory response is massively complex. It involves our immune system – indeed, it is what our immune system is for!
Our immune system, in its simplest form, is a combination of ‘response’ cells and ‘response’ proteins. Doctors will talk of ‘cellular immunity’ and ‘antibody-mediated immunity’ … cells and proteins.
Our immune cells are, mostly, a range of white blood cells (yes, there are heaps and heaps of different kinds – there are white cells that ‘remember’ (they hold immunological memory’) - there are white cells that ‘kill (killer lymphoctes) – and there are white cells that ‘police’, which circulate in the blood stream, sniffing our trouble and acting as the first response team … like the neighbourhood ‘divvie’ van which, when it finds trouble, radios in for back-up … and so it goes on! All these different types of white cells work in a loose ‘partnership’ to provide surveillance and a rapid SWAT response team.
The immune system has a second ‘arm’ … just like our defense forces have three – air, land and sea. The second ‘arm’ of body’s defense is a system of proteins – called ‘antibodies’. These are proteins (often sticky, gluggy, treacly sorts of proteins) which, when an insult is detected (be it bacterial, viral, chemical, toxic – whatever), begin to be made by special antibody-producing cells (called plasma cells). These antibodies (made in response to a detected ‘antigen’ = the ‘stimulus’) attach themselves by ‘receptors’ to the ‘antigen’ (the invader) in the angered area and kind-of ‘neutralise’ or ‘wall off’ the antigenic baddies.
When an ‘incursion’ is detected, our immune system activates …
White cells are ‘attracted’ to the site of the incursion and antibodies are churned out by the plasma cells. Commonly, the battle is waged and won – locally! If the battle site is kept ‘local’, the response will be ‘local’ and after some local irritation and angered tissues, it will settle with no permanent damage done … the zit!
But, if the battle spills over from local to general, spills to other parts of the body … that can be entirely a different issue.
OK … Back to the original first sentence … re-read it … is a complex response of vascular tissue …
The kidney (as an organ) is simply a modified filtering blood vessel which filters excess wastes, salts and water from the blood within it across a filter wall (the glomerular membrane) into a modified collecting system which conducts the filtrate to the exterior … as urine. Easy peasy!
But, NOTE … inflammation is a complex response of vascular tissue … and the kidney IS just a bloody big blood vessel! More than any other organ, the kidney is ‘vascular’ and is an (even the) integral part of the vascular system
So … the inflammatory response – the immune response – these hit the kidneys! And it can hit hard. And it can damage – and it can damage quickly and badly and permanently.
The kidney (as an organ system) bears the brunt of the inflammatory response – and of any damage that battle may leave behind.
Thus – inflammation is commonly the cause (eg: glomerulonephritis) or the aggravator of renal dysfunction. And, as that battle is joined in the kidney tissue itself, the cells and structures of the kidneys get angry. Local irritants are released by angry, damaged kidney cells or by passenger (passing through) cells. These irritants are called ‘cytokines’ … and they have weird names like ‘interleukins’ and ‘chemokines’ … the list is vast and endless. They then cause more inflammation with the kidney tissue … and so a vicious cycle is set up, leading to functional decline and kidney failure.
The less the renal function, the more angry and distressed the kidneys become … and so it goes. Some of these substances, normally excreted by the kidneys, now accumulate, worsening the inflammation. More and more cells are damaged. The battle, once meant as a protective, reparative process, has turned into wholesale war – destroying everything in its path.
You should be getting the picture.
Now … once kidney failure has occurred, dialysis starts!
Haemodialysis uses an artificial ‘membrane’ to take the place of the normal ‘glomerular’ membrane – that filter membrane between modified blood vessel and modified collecting vessel that was briefly described above.
Even though we ‘pride’ ourselves that the artificial membranes we once used (cuprophane) have been replaced by much less ‘immunogenic’ (immune-stimulating) membranes … the now so-called biocompatible membranes … even modern ‘bio-compatible’ membranes are still a little immune-tickling.
Are they better than they were? … undoubtedly yes, but, still, they can still trigger the immune response. So – the artificial kidney membrane itself can be immuno-activating.
Unfortunately, most American dialysis practices still dialyse to a very old and rather poor water standard (the revised AAMI standard) as the water ‘standard’ for dialysis water purity.
In the dialysis process used by single pass machines … and all machines except the NxStage are single pass technology … water (tap water) is passed through a range of particulate filters, carbon filters and softeners, before passing though a reverse osmosis plant to create (supposedly) pure water to mix with a ‘concentrate’ of chemicals to make ‘dialysate’. Dialysate is the ‘constructed’ fluid (which depends on a ripper filtration process) which is then passed, in the opposite direction to the flow of blood inside the dialyser, and on the opposite side of the dialysis membrane, to assist in the removal of metabolic wastes, salts and water during the dialysis process.
If that water isn’t ultra-pure, if it still contains ‘grotty’ things … chemicals, impurities, little shards of bacterial cells or toxic chemicals (endotoxins) that are produced by bacteria … these can pass across the membrane into the blood and set off (trigger) an immune response!
The European standards for the water from which dialysate is made are far, far more stringent than the AAMI standards. We shoot for the European here. The US still accepts AAMI as good enough. Sorry - but it isn’t! We also use an added water protection devise – a Diasafe – to add a further level of protection and filtration. Diasafes are expensive. They need to be changed at least each 3 months but they do help make the water quality for use in the dialysate better. I am sure some US services use these but I am pretty sure not all (or even many) do.
The NxStage, of course, makes on-line dialysate with its PureFlow system … and this is yummy water! So, the NxStage does provide good water for dialysis and will lessen thereby any risks of water-induced immunological stimulation. A tick for NxStage!
One of the enduring efforts in dialysis is to provide ultrapure water (you should hear Carl Kjellstrand on this!) … but at present, in the States, you do not – or not widely so.
One thing we pay too little attention and thought to … and which are known to be potent inflammatory stimuli … are ‘plasticizers’. Plasticisers are substances that leech out of plastics and into any fluid that comes in contact with that plastic. Our lines, our fluid bags (here NxStage - if System One - is not protected) everything is plastic. Let’s not go there - its too complex - but it is true that part of the potential inflammatory stimulus in the dialysis process may come from plasticisers. We have no way, yet, of altering this fact - but we are aware of the dilemma.
I am running out of puff … but, in a nutshell … how do we treat/prevent inflammation?
In pre-dialysis renal disease, our options are still rudimentary!
We can try to identify (and remove) the ‘inflammatory stimulus.
We can treat (with still ‘blunderbuss’ drugs) the immunological response itself: prednisolone and/or immunosuppressant drugs like cyclophosphamide, cyclosporin, azathioprine, mycophenolate etc.
We can remove antibodies from the circulation with untargeted procedures like plasmapheresis
We can – increasingly – try to target the immunological response more accurately, specifically, with newer but horrendously expensive agents (drugs) called monoclonal antibodies (drugs that end with the suffix ‘mab’)
Or we can watch, sadly and impotently, as renal function declines … wishing, knowing, we should be able to do more, but being unable to.
That’s why so many end up on dialysis
Then after dialysis starts …
We can use as biologically compatible a membrane as we can … we use polysulphone (which is pretty good and is as biocompatible as any)
We can assure as pure or, better, ultrapure water as we can – aiming at the European standards and eschewing the old, poor standards of AAMI … see our Australian guideline document at our CARI guideline site http://www.cari.org.au/DIALYSIS_adequacy_published/water_quality_for_hemodialysis_jul_2005.pdf
We (can) check our systems for endotoxin – and we try to do that with better techniques and more often than most.
We can do heaps to make the systems we use as minimally immunogenic (immune stimulating) as we can
At the end of the day, the immunological response is both a protector and a wrecker. It is a double-edged sword. For most, we benefit from its protection. For some, with kidney disease, it turns against us – with profound consequences
For you, the individual, with your disease, it depends on your disease how much this all applies to you – or what, even if it does, can be done to help. Often this is a big fat nothing.
For those on dialysis – ensure through your local teams that you have minimally immunogenic dialysis systems in place.
That, MooseMum, is about all I have the energy to provide. I hope it has been of some help or educative value
That was utterly and stupefyingly OUTSTANDING! I am very grateful. I can well imagine the time, effort and energy that took. Thank you, it explained a lot. Thank you.
Phew … just corrected and added a bit more. Hope it answered some of your questions
Hi Moosemom, I just finished reading an excellent book called Deep Nutrition: Why Your Genes Need Traditional Food by Catherine Shanahan, MD. ( http://www.amazon.com/s/ref=nb_sb_noss?url=search-alias%3Daps&field-keywords=deep+nurition&x=0&y=0 ). In it, she explains exactly how sugar and vegetable oils trigger inflammation and a cascade of events that damage the body and lead to illness. Even with CKD, I can’t think of any reason why you wouldn’t be able to follow her suggestions, if you were so inclined. If you’re into this kind of thing (and I sense from your questions that you are), you may want to read this and see what you think.
Dori is right in what she says about the way our diets have changed. Our immune systems are eons old, and have been trained slowly over millennium after millennium to resct to an respond to the common noxious stimuli found in our natural environment – including the then commonly encountered bacteria and viruses.
However, from the 18-19th century and in particular the onset of the industrial revolution, we began to change our environment. The pace of this change has been exponential – especially in the last 50-75 years – with a range of chemicals, toxins and effluents discharging into the air we breathe, the water we drink, and into the earth that feeds the plants we eat … or the animals eat, that we then eat.
The new toxins and chemicals, the new bacterial species that have been morphed by the antibiotics we use on ourselves and on the animals we feed upon, the new growth modifying hormones we feed our chickens and cattle … the list is endless … all are challenges to a millennia-old immune system that is neither prepared nor trained to respond. Then, if the immune system does respond, it responds ‘off-key’, ‘out-of-tune’ and in ways which – though it IS trying to do the right thing – can be as potentially harmful to its host (us) as it intends to be protective.
Much of renal disease is immune-based. Much of renal disease is the result of immunological injury to the kidneys. This is why so many of the treatments we use in renal disease are targeted at the immune system … prednisolone, the immunosuppressive drugs, plasma-exchange, the monoclonal antibodies … the list goes on. But, to date, these treatments are like using a broadside to take out the radio mast … overkill, untargeted, and as like to cause unwanted widespread collateral damage as to bop just the specific offender on the nose. Yet, it is all we have. In years to come, we may target better, target more specifically … but I fear the slew of nasty things that outwit, or harm, or are simply not picked up by our immune systems will always be two steps ahead as we try to play ‘catch-up’.
Another aspect we forget is that the kidneys concentrate … not as in ‘focus’, but as in ‘increase’ … whatever they filter! Humans make about 180 litres … yes, 180 LITRES of plasma ultrafiltrate a day across the glomerular membranes. That’s a staggering volume of fluid. As 1 litre = 1 kilogram, that means 180 kilograms of fluid = > twice the total weight of an average human (= 70 kilograms). If your kidneys (how wonderful they really are) did not concentrate the wastes but reabsorb almost all of that fluid, you would pee out your body weight twice a day, every day.
So … the kidneys ‘concentrate’ that plasma ultrafiltrate many, many times over, reabsorbing almost all of it as the plasma filtrate is passed along the tubular system of the kidneys. Salt and water is avidly sucked back in … but wastes are not. How cool and clever is that! No wonder I wanted to be a nephrologist. The kidneys are, truly, marvelous.
But … as they remove salt and water from the tubular fluid, reabsorbing it into the body, the filtered wastes become ever more concentrated such that the final urine passed is ~1.5 litres a day (ie: 178.5 litres of water/day is reabsorbed).
Again but … if harmful chemicals are ingested, breathed in, absorbed into the blood stream then filtered out by the kidneys, those same wonderful kidneys will (unwittingly) be concentrating those toxins many-fold as they pass down the reabsorption pathways of the kidney after glomerular filtration. This concentrating process can, thus, inadvertently elevate the levels of loxins (and drugs too) to very high concentrations within the kidneys – many fold the concentrations they are intended to reach.
We now know a lot about drugs and the kidneys (and by drugs, I mean therapeutic drugs). We know the doses that are safe – and those that aren’t. We know what risks harming the kidneys and what is harmless. What we don’t know is what effects some of the ‘unknowns’ have. What was it that that Rumsfeld man said about knowns and unknowns … all I remember was that is was almost as convoluted as the tubular structures of the kidneys – but not nearly half as clever!
Nevertheless, we can take some steps to help out troubled and confused immunity. We can chose to eschew prepared, mucked-about, tampered-with foods. Foods with all sorts of additives, colourings, things to make them look appealing but which, as protection against, our immune systems are neither trained nor savvy.
Good, wholesome, un-mucked-with food and drink will always win out over prepared, preserved, chemicalised’ foods. Diet does matter. But, I fear it may be naïve to think that that alone is likely to protect us, our immune systems or our kidneys when we breathe, bathe, live constantly in a new and frightening chemical soup of our own making.
That sounds pessimistic … and to an extent it is. But, by all means go natural! Every little bit helps. But, will a change of diet be enough to aid and protect the immune systems of you, your neighbour, or ‘us’ as a species? Probably not!
Thanks for that, Dori. I have read a book about the inflammatory properties in foods and how omega-3 are supposed to combat that. I will check out the book you recommended, though. I am interested in foods that are nutritious and unadulterated. I like my food to be simple and unprocessed.
I understand that much of kidney disease, like my fsgs, is immunological. I have been treated with cyclosporine although once my egfr dropped below 20, my neph felt it was now doing more harm than good, so I no longer take it. But that leads me to my most fundamental question of all…
It may have just been a coincidence, but the timing of events has led me to believe that my pregnancy somehow “triggered” a funky immune response that has lead to the near destruction of my renal function.
I’d always had checkups and had never been made aware of any renal problem. When you’re female, you tend to have these annual exams that would catch, I presume, signs of a problem. I was 23 weeks pregnant when I had my first weekly pre-natal checkup. In the UK back then (1991), a pregnant woman would have a monthly checkup, and then they’d become weekly in the latter stages of pregnancy. The night before, I had noticed that my ankles were a bit swollen. I mentioned this to my GP, he checked my urine for protein, told me to go home, go to bed and don’t even think about returning to work (I was a reinsurance broker for underwriters at Lloyd’s of London). I did, and the district nurse came to my home the next day, tested my urine and said she’d never seen the stick turn that color before.
I immediately landed in the hospital for pre-eclampsia and spent the next 6 weeks there.
After delivery, I was still spilling protein.
Six months later, I had a renal biopsy which confirmed fsgs.
I know there is no known cause for fsgs (unless, maybe, if other family members have it and it is therefore hereditary), but since fsgs is immunological, and since pregnancy does very odd things to your immune system so that your body won’t reject the baby, and since my fsgs was confirmed after pregancy, and since I had no signs of renal insufficiency before I got pregnant, could fsgs and pregnancy be linked?
I’ve been wanting to ask that question for 20 years. I know you may not have an answer, but what would be your educated guess?
I promise…that’s my last question for a while. You’ve spent enough time on my queries.
In a word … yes … it is possible.
There is data to support that theory … anecdotal, to be truthful … but, lots of anecdotes begin to make a pattern. So, yes, it is certainly possible.
You are not the 1st, and you won’t be the last, where pregnancy has been thought to be the trigger. Some have suggested that in certain women (? who, ? why), contact of amniotic fluid with the maternal immune system may trigger an immune response which then sets off the train of immunological events that is FSGS.
A circulating immunologically active protein has been suggested as a cause - with some ‘presumptive’ evidence taken from the fact that plasma exchange can control or permit control of FSGS.
It certainly sounds as if you had pre-eclampsia, good and proper, but immunological glomerular disease emanating from or after pregnancy is not quite as rare as it may seem.
To be truthful … we just don’t know. But other ‘anecdotal cases’ are certainly ‘out there’. Whether you … and whether your FSGS … no one will ever be able to say for sure.
But , as I said - you ain’t the 1st!
That’s pretty much what I suspected.
The tragedy doesn’t end there.
My son ended up being autistic. I could now ask if maternal renal insufficency during gestation might be a cause for autism, but I suspect that’s a question that might be above your pay grade.
Thank you for your time!