In chronic kidney disease in humans, uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage.... (U-Tox for short) play such an important role that a European research group is dedicated to this topic alone. This research group defines uraemic toxins as follows:
- blood and tissue levels of the toxin must be substantially elevated during chronic kidney disease (CKD).
- high concentrations of the toxin are directly related to one or more symptoms. This means that the toxin triggers the symptoms.
- the biological activity of the toxin, i.e. its harmful effect, should be confirmed in laboratory tests at high concentrations, as found in CKD.
- the biological mechanism responsible for the harmful effect should be known. It can be seen that some uraemic toxins exert their damaging effect only at high blood levels.
Direct harmful effects of indoxyl sulphate
The harmful effects of indoxyl sulphate and para-cresyl sulphate, for example, have already been described several times (see blog post “Uraemic Toxins“). These uraemic toxins can exert their harmful effects directly, regardless of their blood and tissue concentration. Ultimately, however, accumulation in blood and tissue due to reduced excretion in CKD is the reason for the symptoms that occur and the progression of the disease. Precisely because indoxyl sulphate and para-cresyl sulphate directly damage the kidneys and thus lead to higher mortality.
Fluctuating urea level
This correlation between higher mortality and ureaUrea is the nitrogen-containing breakdown product of protein metabolism. The nitrogen from the proteins is converted to ammonia in the liver, which is combined with carbon dioxide to form urea. This is continuously excreted via the kidneys but also via sweat. Urea is one of... concentration could not be proven so far. Urea is a naturally occurring product of protein metabolism. Its blood level is not only dependent on kidney performance, but also on a protein-rich diet, the fluid content in the body (e.g. dehydrationA deficit of total body water. Dehydration can be caused by excessive fluid loss, for instance via the kidneys in CKD, or by insufficient fluid intake....) and intestinal bleeding. This means that the urea concentration per se is subject to fluctuations. Even in experiments, the harmful effect of urea could not be proven so far. On the contrary, urea was assumed to have a positive effect, so that some patients were even administered urea orally.
Alteration of the intestinal flora
The authors Verdier, Soulage and Koppe (2022) report that in large-scale experiments, elevated blood levels of urea, as in CKD, proved to be a trigger for diabetes, especially in obese individuals. Also, high concentrations of urea showed a change in the intestinal flora in mice. The connection between the production of uraemic toxins such as indoxyl sulphate and para-cresyl sulphate is directly related to the intestinal flora. Both uraemic toxins are produced from protein metabolism through the breakdown of amino acids by intestinal bacteria. Since the uraemic toxins originate in the intestine, but trigger their harmful effects on the kidneys (and other organs and tissues), they are also referred to as the gut-kidney axis (see blog post “The intestines aren’t just charming“). It is these intestinal bacteria that can predominate in CKD and lead to an imbalance of the intestinal flora (so-called 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....). This effect is also caused by an increased indoxyl sulphate blood level.
Urea as a mediator
In CKD patients, high levels of urea have been associated with central nervous disorders such as depression. Cognitive impairment has also been reported with elevated levels of indoxyl sulphate (see blog article “When CKD fogs the brain“). Urea also acts as a mediator for other damaging substances that appear in CKD, leading to connective tissue remodelling of the kidneys and reduction in kidney function. Connective tissue remodelling of the kidneys is a major reason for reduced kidney function because connective tissue scars are non-functional.
Especially high amounts of urea – as they occur in chronic kidney disease – have this effect.
Urea as an indication of uraemic toxins
In veterinary medicine, the blood urea level is routinely examined as part of the kidney profile in CKD cats. For diagnosis and classification into the four CKD stages, the IRIS (International Renal Interest Society) uses the creatinineCreatinine is a breakdown product of muscle metabolism. Its blood level is dependent, among many factors, on age, weight, nutritional status and muscle mass. Hence, creatinine levels in the blood vary from individual to individual. Creatinine is continuously excreted in the urine. Increased blood creatinine... value as a guide. The creatinine value is more reliable, as the urea value is subject to various fluctuations. The urea value is considered more of a proxy for the level of uraemic toxins. Uraemic toxins such as indoxyl sulphate can meanwhile be measured independently.
- Verdier, V.; Soulage, Ch. O. & Koppe, L. (2022): New clinical evidence for urea toxicity. Nephrology Dialysis Transplantation (37), S. 1–4. https://doi.org/10.1093/ndt/gfab269