Chronic fatigue – example: the dialysis patient

This column is written by Stig Bengmark – Professor Emeritus, scientist, lecturer and writer. Read more of Stig Bengmark’s columns here.

Anyone who has not experienced chronic fatigue has no idea how horrible it feels – in fact, it’s often worse than physical fatigue. But unlike physical fatigue and pain, chronic fatigue is almost impossible to treat with medication – often it only gets worse if you try. I’ve had a long life and I’ve been a doctor since 1956, but I actually had no idea how wide-ranging chronic fatigue is or how deadly it is for quality of life before I started writing columns. A lot of chronically fatigued people contact me in the hope that I can help them ‘out of this hell’.  Unfortunately not – I gave up my work as a doctor when I retired in 1994 and I don’t have the resources anymore, not least in regard to time. I’ve chosen to devote all my time to research, teaching, and public education. And I’m sure I can help more people if I address them in the tens of thousands at a time.

A lot of people have investigated chronic fatigue – notably among dialysis patients. This is how the excellent researchers at Karolinska Institutet, Södertälje Hospital, and Linköping Hospital described chronic fatigue in 2003:

The nurses, Katarina E Andersson and Pernilla Naumann, at the University Hospital in Malmö went through all of the international literature on fatigue in kidney patients a few years later and discovered a lot of statements about how these patients really feel. Unfortunately, it only went as far as these observations – not much has been done to address it. The same is true for patients who are on waiting lists for a transplant of their liver or lungs, for example. With colleagues in London, we looked for research funding for reconditioning the intestines of patients who are on waiting lists for a liver transplant, but this was something the National Research Council didn’t feel they wanted to prioritise – so the study was never done. This happens to me over and over again!

The brain places its burden on the gut

The typical chronically fatigued person has lived a stressful life, eaten negligently and not bothered to exercise. No organ has as many nerve connections with the brain as the gut – billions of nerve fibres connect it directly to the brain and in stressful situations they ‘spew’ the stress hormones, adrenaline and norepinephrine, into the intestine. The good bacteria can’t withstand these neurotransmitters – ‘mass murder of good bacteria’ occurs – and several billion bacteria can often disappear within an hour or so. For people who already have a poor collection of good bacteria and/or are taking medicine, the situation is even worse.

Stressed-out people rarely give themselves time to eat the food that the good bacteria need – perhaps they’re too tired to also prepare ‘healthful’ food. It’s not uncommon for fast food to replace real food – such food is absorbed high up in the small intestine and consequently little of it is left for the hungry good bacteria that are so important for us to have a well-functioning immune system and good protection against chronic disease.

‘Well-behaved’ good bacteria

Even when they don’t get any food, the good bacteria are still well-behaved – they absolutely do not cause any trouble, they just kindly disappear in the utmost silence and let the malignant bacteria, such as coliform bacteria, take over. The bad bacteria, on the other hand, are actual terrorists who immediately begin to produce illness-inducing toxins and spread into the rest of the body in search of food, they paralyse the immune system and, at least temporarily, take control of the body. The situation is exacerbated if you eat unhealthy food and especially food that contains various types of poisons that are released by heating.

The main responsibility for our health actually lies with our microbiota!

At around 2 kg, at best, the health bacteria we have, or at least should have, in our gut, called the microbiota, have to be taken care of with, among other things, the daily supply of food that the good bacteria want and need for their growth and continued existence (every day 1-2 kg of vegetables, preferably raw, containing lots of nutrients, such as magnesium, that are necessary for the good bacteria to be able to multiply and work). Unfortunately, people don’t eat this type of food often enough nowadays, and people with kidney disease are no exception. Most people, including with kidney disease, are instead content with factory-produced food/refined foods (bread, pizza, pasta, cooked rice, cooked root vegetables, etc.), which are absorbed in the upper small intestine, and of which very little reaches down to the large intestine and the hungry bacteria, that live there.

Western factory-made food is definitely not a ‘diet for bacteria’ – with this type of diet, the intestinal flora quickly takes a negative turn, the good bacteria voluntarily leave and let the so-called bad bacteria take over to dominate the gut and the body in general. Dietary advice at hospitals, like the food on offer, is terribly outdated, which goes against the ambition to help our patients.

Chronic debilitating fatigue is very common among dialysis patients

Patients with chronic kidney disease and in need of dialysis are likely to suffer from chronic fatigue to the same degree as a lot of people with other kinds of chronic fatigue. Other people may have suffered from chronic fatigue for completely different reasons – perhaps they’ve suffered from a severe infection in the kidneys or other organs, such as the lungs or liver, and often they’ve been so seriously ill that they’ve been treated in intensive care for some time. This has led to their kidney function being more or less wiped out for the rest of their life, and the condition cannot then be cured without a transplant. Dialysis is a sustained treatment, which has been and still is a great blessing. However, the dialysis is by no means a complete solution, but rather an attempt to filter out unhealthy substances from the body, many have been brought in via diet, but the vast majority of the toxins – around a hundred – have been caused by malignant bacteria in the intestine.

The dream is that dialysis will totally replace the function of the kidneys – but it’s a long way off

Even if new membranes are created all the time, we’re far from being able to produce something that resembles a kidney in terms of function. Kidney dialysis is still mostly just filtering and so far no one has discovered a filter with the ability to remove all the toxins created by the bacteria. Of the approximately 100 bacterial toxins identified, one to two dozen are ‘resistant’ to filter treatment – the common feature among these is that they bind to one or more proteins. The image below lists a number of so-called uremic (bacterial) toxins and clearly shows how limited current dialysis methods are in terms of the ability to eliminate some of these bacterial toxins – some very toxic ones remain in the body and are probably the main cause of the chronic fatigue that afflicts sick people, and also constitute a significantly increased risk of a person with kidney disease developing various conditions of chronic disease – ranging from cardiovascular disease to cancer and diabetes.

Optimistic dialysis filter researchers claim we’re rapidly approaching the time when the dialysis membrane will start to resemble real kidneys – I personally think that’s a long way off. We’ll most likely never get there – don’t forget that the kidney has functions other than filtering – for example, it also has many important synthesising functions.

The microbiota’s speciality is actually breaking down proteins and eliminating protein-bound toxins

The microbiota has an ‘almost unending’ amount of duties. One very important task, for example, is extracting nutrition of different types from plants and, for that matter, also foods that come from animals: nutrients, antioxidants, and vitamins. Another special and very important task for the microbiota is efficiently breaking down lots of different proteins which we’ve ingested with our food – a specialty that becomes especially important with severe kidney disease. Breakdown of proteins always causes the release of toxins, known as uremic toxins, which are a heavy strain for anyone, but especially for people with kidney disease, if they are left in the body.

The microbiota efficiently eliminate uremic toxins

It’s important to know that the microbiota can efficiently facilitate both the breakdown and elimination of uremic toxins – a property that would be advantageous in the treatment of kidney patients – but such functions are completely lacking in dialysis treatment. Gut reconditioning, as I like to call it, should be welcomed as a worthwhile complement to a dialysis treatment. A properly-functioning microbiota can be expected to radically reduce the degree of inflammation in the body, increase the effectiveness of one’s own immune system, and indirectly protect against recurrent infections, chronic diseases and premature ageing, for example. Patients suffering from chronic diseases such as Alzheimer’s disease, ADHD, diabetes, chronic lung disease (COPD), chronic liver disease and chronic kidney disease – often called ESRD (end stage renal disease) – actually almost never have a properly-functioning microbiota and should be given a daily supplement of synbiotics (a combination of prebiotic fibre and specific lactobacilli/probiotics.)

Gut reconditioning with Synbiotics can be expected to:

• Eliminate uremic toxins
• Eliminate the bacterial toxin, endotoxin, which contributes to the causes of a lot of acute and chronic illnesses
• Eliminate external toxins such as from heating, environmental toxins, hormone residues, medicine residues, etc.

As I see it, patients with chronic kidney disease are, unfortunately, often advised to be careful about consuming fruit, mostly to counteract an excess of the mineral potassium that can easily occur in a kidney patient. It is, of course, a significant disadvantage that this also limits the supply of various nutrients, such as antioxidants and minerals, mainly magnesium but also short fatty acids, which are vitally important for the growth and multiplication of the good bacteria in the gut. It also contributes to the increased risk of leakage of toxins through the intestinal wall and into the body.

Eliminating high ‘inflammatory pressure’ is especially important for dialysis patients

Most of today’s dialysis researchers are chiefly focused on improving the membrane function of dialysis filters. One wonderful exception is Professor Peter Stenvinkel, a nephrologist at Karolinska and Huddinge Hospital, one of the world’s foremost experts on inflammation and kidney disease. Stenvinkel has instead focused his research on the clear connection that exists between diet, obesity, inflammation and kidney disease – and probably also chronic fatigue. He’s successfully explored this very complex phenomenon.

Large amounts of disease-causing bad gut bacteria are common among dialysis patients

In fact, it’s well known that dialysis patients suffer from a high level of so-called ‘oxidative stress’, which is known to create conditions for complications such as cardiovascular disease, metabolic syndrome, weight loss/anorexia, anaemia, and many other diseases and complications. Not only uremic toxins but some or all of the intestinal bacteria are often found in the blood of dialysis patients – a recently published study found the DNA of disease-causing intestinal bacteria in no less than 20% of dialysis patients (Wang F et al. Nephrology 2012; 17: 733-738). Often, malignant bacteria such as Klebsiella spp, Proteus spp, Escherichia spp, Enterobacter spp, and Pseudomonas spp are also found in the blood of dialysis patients, in parallel with signs of greatly increased inflammation in the body and also impaired metabolism: increased D-lactate in plasma, increased C-reactive protein and increased interleukin-6 levels – the latter an important sign of increased inflammation in the body.

Dysbiosis and leaky gut – a bigger problem with haemodialysis than with peritoneal dialysis

Identifying and eliminating ‘organic waste products’ is the main goal of dialysis. Between 90 and 100 of these waste products have been identified – the attached picture lists the most common and widespread.

The majority of these come from the breakdown of amino acids, not least tryptophan and tyrosine, which are often ingested in far greater amounts than the body needs and which are also poorly broken down in situations where the gut flora is functioning poorly, which, as I’ve said, is pretty much always with dialysis patients. Tryptophan and tyrosine are found in large amounts in seeds, nuts, different meats, cheese, shellfish, fish, and eggs. And tyrosine is also found in large amounts in seaweed (spirulina). Leakage of bacterial toxins such as indoxyl sulphate and p-cresol sulphate has been reported to be significantly higher in patients undergoing haemodialysis than in those undergoing regular peritoneal dialysis (Pham NM et al. Clin J Am Soc Nephrol 2008;3:85–90).

A known problem for decades – but little has been done about it

The intestinal problems of kidney patients have been known for decades and, with this knowledge, it’s inconceivable that efforts have not been made to do as much as could reasonably have been done. Attempts to recondition the gut, reduce the production of toxins, and stop the leakage of bacterial toxins into the body have been almost completely avoided.

It’s very pleasing to see that just the supply of prebiotic fibre (excellent food for good bacteria) in such a comparatively small amount as 10-20 grams per day, has already been proven to significantly reduce the amount of the bacterial toxin p-cresol sulphate in the blood (Meijers BK et al. Nephrol Dial Transplant 2009;25:219–224). Adding plant fibre is a simple and very inexpensive effort to make – a measure that should be possible to apply immediately. This observation should also be leading to studies of how different types of ‘magic fibre’ can dramatically contribute to the well-being of kidney patients. It may be interesting also to note that my synbiotic composition, Synbiotic 2000, contains no less than 10 g of four different kinds of highly bioactive prebiotic fibre.

Probiotics for dialysis patients – strong and positive effects

Back in the infancy of the probiotic era, a small study was done with promising results. Eight haemodialysis patients were given Lactobacillus Acidophilus, which is very commonly found in yoghurt. The treatment effectively reduced the toxin, dimethylamine (DMA), in the blood (from an average of 224 to an average of 154 micrograms/dl (p <0.001) (Simenhoff ML Miner Electrolyte Metab 1996; 22: 92-96, Dunn SR et al Int. Dairy Journal 1998; 8: 545-553). One remarkably important observation was that, at the same time, it was possible to observe a 50% reduction in the level of the carcinogenic poison, Nitrosodimethylamine, in the blood (from an average of 178 to an average of 83 ng / kg). It was thought that these observations would stimulate a flood of studies using more specific probiotics and synbiotics, but this did not happen. Instead, it seemed like everything possible was done to forget these important observations – it took around another 15 years before the next study came about.

The first study with synbiotics on dialysis patients was, in fact, first published in 2011

This study has many shortcomings, it uses too small a dose of lactobacilli, and was also carried out on too few patients – only nine – and, in addition, for too short a period – only two weeks. They tried a synbiotic composition with a relatively low dose of both lactobacilli and fibre: 108 Lactobacillus casei strain Shirota, 108 Bifidobacterium breve, (Yakult) and just 4 g of galacto-oligosaccharides – a well-known and dependable prebiotic. Despite all these disadvantages, it reports significantly lower levels in the blood, of the worst mega-poison p-cresol, as hoped for, but also a very desirable reduction in constipation, something that is often a problem for dialysis patients (Nakabayashi I et al.  Nephrol Dial Transplant 2011;26:1094-1098).

Unique possibilities for treatment with synbiotics to reduce the level of bacterial toxins in the body

The following year, 2012, an analysis was published of everything that had been previously published regarding the treatment of dialysis patients with pre-, pro- and synbiotics – something called a meta-analysis. This analysis states, as already indicated above, that the observations in each individual study are based on far too few patients, too low doses of lactobacilli, and far too short study periods. Despite this objection, it’s noted that there are strong indications that synbiotic treatment effectively reduces the levels of the ‘baddies’ in the blood – the protein-bound bacterial toxins, indoxyl sulphate and p-cresol sulphate (Rossi M et al. Int J Nephrol 2012;2012:673631).

In a 2013 study, 16 Korean children with kidney disease were treated for 12 weeks with the well-known Italian probiotic composition VSL# 3 (consisting of eight different good bacteria at a high dosage). Blood levels of indoxyl sulfate and p-cresyl sulfate were measured after 4, 8, and 12 weeks but unfortunately without success (Hyun HS et al Korean J Pediatr 2013; 56: 159-164) – it was the probiotic drug VSL that was being tested, a composition which has often been proven to be ineffective.

Pro- and synbiotics are effective at ‘beating down’ inflammation

Last year, a Taiwanese study was published which offers some hope. In this study, over six months, 39 patients were given either a probiotic composition consisting of a billion parts of three different bifidobacteria and one billion parts of Lactobacillus plantarum A87, or maltodextrin as a placebo. A number of inflammation-indicating markers (cytokines) and endotoxin levels were measured before and after the end of treatment and showed significant improvements in the group treated with the probiotic. Renal function was also better preserved in the group treated with the probiotic (Wang IK et al Benef Microbes. 2015;6:423-30). This study is also based on too little patient material, does not include any extra added fibre, and above all there is far too small an amount of lactobacilli – Synbiotic 2000 contains many times more good bacteria and also a large amount of bioactive fibre.

Synbiotic treatment is an excellent complement to dialysis and also, most likely, transplants

New filters have enabled evermore effective dialysis treatments, but significant problems remain, not least with regard to the effective elimination of azotemic toxins (nitrogen-containing substances such as urea and creatinine), unusual substances which are highly protein-bound (Davenport A Hemodial Int. 2014 Oct;18 Suppl 1:S43-7). The ability of dialysis to eliminate these is a long way off from where we’d like it to be. This applies, among others, to P-cresol, which is particularly associated with a high degree of inflammation, an increased degree of cardiovascular disease in non-diabetics, and increased mortality rate among dialysis patients (Krieter DH et al Nephrol Dial Transplant 2010; 25: 212–21, Sirich TL et al. Semin Nephrol. 2014 Mar; 34 (2): 106-17.) – and, notably, an often observed, very painful fatigue among dialysis and sometimes also transplant patients. According to Sirich et al (2014), there are also a number of almost unidentifiable protein-bound toxins, which dialysis eliminates poorly and whose clinical effects are far from clear, and which may well have even greater negative effects in the body than even pCS. Synbiotic treatment offers great opportunities for eliminating exactly these protein-bound toxins and thereby offers a significant complement to an otherwise successful dialysis treatment for advanced kidney disease.

At the time of writing, one very interesting study has been presented in preparation for a larger study. This showed a clear reduction of one of the ‘baddies’, p-cresyl sulphate (PCS) with a daily treatment of dialysis patients with 90 billion good bacteria (about a fifth of what I use in Synbiotics 2000) plus 15 grams of important fibre – a real dose! An increase in the number of good gut bacteria was also shown.

I would very much like to try my Synbiotic 2000, which has shown such unique anti-inflammatory properties and which, among other things, has been shown to remove negative effects on the brain, on liver disease patients – what’s known as a ‘foggy mind’ a phenomenon that other chronically ill such as diabetic patients also often experience.

For at least 15 years, I’ve been wanting to conduct clinical trials with Synbiotics on chronic kidney disease patients. I have appealed to the profession in both the UK and Sweden without any success. There are two groups of patients in particular that have proved particularly impossible to study – those with HIV and those with kidney disease. Business seems to be particularly good at guarding its territories in these areas. After a lot of ‘lobbying’ a couple of years ago, we conducted a small study on HIV in California – but dialysis patients still remain to be studied.

I’ve visited, lectured to, and tried to motivate kidney doctors around the world – from leading clinics in Stockholm and London to clinics in various developing countries, unsuccessfully. There’s been no lack of enthusiasm among kidney doctors, but always at the ‘last minute’ there’s some company, e.g. dialysis or a pharmaceutical company, willing to pay large sums, something I cannot offer, for ‘an absolutely necessary’ trial of a new drug, a new filter, a new solution or the like.

Is there anyone who can give me any advice on how to make progress with this?