As kidney function declines, concentrations of uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage.... such as indoxyl sulphate increase, setting in motion a self-reinforcing cycle that leads to progressive impairment of kidney function.
How do uraemic toxins develop?
Uraemic toxins are metabolic degradation products that can have harmful effects if they accumulate in the body. There are a large number of such uraemic toxins. Two very well-known uraemic toxins are indoxyl sulphate and para-cresyl sulphate. Both are produced by the microbial digestion of proteins and are therefore toxic degradation products of protein digestion.
Proteins consist of amino acids. Proteins are vital for cats, as cats are obligate carnivores. This means that cats obtain their vital energy from proteins. Their metabolism is so protein-orientated that they digest their own muscles if they don’t get enough protein from their diet. Protein digestion permanently produces uraemic toxins. After ingestion of dietary proteins, tryptophan is broken down into indole by the intestinal microbiota, mainly in the distal colon, where a higher pH favours optimal enzyme activity. There are more than 85 species of bacteria that produce indole. The amino acids phenylalanine and tyrosine are also broken down into p-cresol by different intestinal bacteria of the intestinal microbes. Indole and p-cresol are precursors for the uraemic toxins indoxyl sulphate and para-cresyl sulphate, which are only formed in the liver.
Indole and p-cresol are transported from the intestine to the liver. After being metabolised in the liver, the two uraemic toxins are transported to the kidneys, where they are usually excreted in the urine without any problems.
Uraemic toxins have long been known to be responsible for a high mortality rate in people with kidney disease. For some years now, this connection has also been recognised in feline medicine. Uraemic toxins are partly responsible for uraemiaA raised level in the blood of urea and other urinary substances, which in chronic kidney disease can no longer be adequately excreted due to impaired renal function (glomerular filtration rate). This leads to renal damage due to uraemic toxins, toxic urinary substances The symptoms... (= accumulation of metabolic waste products that are normally excreted by the kidneys) in chronic kidney disease, which is accompanied by clinical symptoms. Indoxyl sulphate and para-cresyl sulphate lead to further kidney damage due to nephron loss and thus contribute to the progression of CKD.
Gut-kidney axis
In chronic kidney disease, the resulting uraemic toxins cannot be sufficiently excreted and accumulate in the blood. From the blood, they enter various organ systems and cause damage. This also affects the kidneys.
The gut-kidney axis describes the effects of gut health on kidney health. Indoxyl sulphate is an important component of the gut-kidney axis. It accumulates back into the blood in CKD because the kidneys are no longer able to excrete sufficient amounts of this uraemic toxin. In the kidneys, indoxyl sulphate leads to inflammatory processes and increased connective tissue formation (renal fibrosis) in the nephronsNephrone sind die Filtereinheiten der Nieren...., which destroys them. As a result of this kidney damage, indoxyl sulphate favours the progression of chronic kidney disease (CKD).
On the other hand, indoxyl sulphate and para-cresyl sulphate cause a shift in the intestinal bacteria so that the natural intestinal microbiomeAll microbes on or within an animal’s tissues, for instance in the intestines (intenstinal flora = the totality of all microorganisms that colonise the intestine). It includes bacteria, protozoa, fungi and viruses.... becomes unbalanced. This leads to dysbiosisImbalance of organisms of the the microbiome (all microbes on or within an animal’s tissues), for instance the imbalance of the intestinal flora as part of the microbiome...., an imbalance of the intestinal bacteria with negative consequences for the intestine. This impairs the supply of sufficient short-chain fatty acids to the intestinal cells, which are normally produced by the healthy intestinal bacteria. The connection between the intestinal cells (tight junctions) is severely disrupted, so that the intestinal barrier breaks down and uraemic toxins and other toxins can increasingly pass through the intestinal wall. In addition, indoxyl sulphate promotes the growth of precisely those bacteria that produce indole and p-cresol, so that even more uraemic toxins are formed. However, these additional quantities of indoxyl sulphate or para-cresyl sulphate can no longer be excreted by the chronically ill kidneys, creating a vicious circle.
Studies have shown that the concentration of indoxyl sulphate increases from IRIS stage 2 and that the concentration of indoxyl sulphate in the blood increases exponentially with each IRIS stage.
Harmful effects of uraemic toxins
Increased concentrations of uraemic toxins such as indoxyl sulphate also have harmful effects on other organs, which are usually accompanied by clinical symptoms.
In the cardiovascular system, indoxyl sulphate and para-cresyl sulphate lead to inflammation of the blood vessels and pericardium. Aortic calcification may occur. Uraemic toxins are also involved in the increase in blood pressure.
Indoxyl sulphate reduces the production of erythropoietinErythropoietin, abbreviated to EPO, is a growth factor that stimulates red blood cell production. EPO can be produced biotechnologically and administered for kidney failure or after chemotherapy.... and thus the formation of red blood cells. The survival time of the red blood cells is also shortened by indoxyl sulphate. This contributes to anaemia in CKD. Uraemic toxins such as indoxyl sulphate can promote diabetes.
In the brain, uraemic toxins cause fatigue, tiredness and behavioural changes similar to dementia (uraemic encephalopathy). If the blood level of indoxyl sulphate falls, this effect was reversible in one study. Comatose states may also occur, usually indicating the approach of the final stages of the disease.
P-cresyl sulphate promotes susceptibility to infections by influencing the immune system.
On the bone, indoxyl sulphate supports the release of phosphate and thus hyperparathyroidism, also by promoting parathyroid hormoneParathyroid hormone (PTH) is a hormone secreted by the parathyroid glands, which regulates calcium levels in the blood. PTH is secreted in response to low blood calcium levels (hypocalcaemia). An increase in calcium concentration above the normal value inhibits PTH production (negative feedback). PTH stimulates..., and is therefore involved in mineral and bone disorder (MBD) in the context of CKD.
In the muscles, indoxyl sulphate causes muscle atrophyWasting away of tissue, a reduction in the volume and/or size of tissues or organs..... This also leads to muscle weakness and can cause tremors and cramps.
Uraemic toxins can be deposited in the mucous membranes of the gastrointestinal tract and then lead to bad breath in cats. This can impair eating. In addition, ulcers and the resulting vomiting, nausea and diarrhoea can occur due to accumulation in the stomach and intestinal mucosa. Digestive disorders are also caused by dysbiosis in the intestine. This means that indoxyl sulphate and para-cresyl sulphate impair the natural intestinal flora.
The indoxyl sulphate blood level does not reflect the level of indoxyl sulphate in the tissue, even if these correlate to some extent. The tissue level may be higher. In addition, there is a high variability in the indoxyl sulphate blood level because the concentrations of indoxyl sulphate constantly change between the tissues and the blood level. High blood level variability is especially true for low indoxyl sulphate levels.