MORTALITY ALLIES

Mortality allies – elevated FGF-23 and indoxyl sulphate in cats with kidney disease associated with a poor prognosis

A study conducted in the summer of 2019 revealed, that mortality in cats with chronic kidney disease (CKD) is directly correlated with FGF-23 blood levels. An increased FGF‐23 concentration (see found to be associated with shorter lifespan in cats with CKD and results in the deposition of calcium within organs of the body. FGF-23, fibroblast growth factor–23, is a mediator involved in calcium and, especially, phosphate metabolism. responsible for reducing phosphate and keeping 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... (see The Devil is in the “P”) in check. To do this, it requires a co-factor called α-klotho. This co-factor is suppressed by indoxyl sulphate.

Elevated blood phosphate (hyperphosphataemiaIncreased phosphate in the blood.) is one of the central problems of CKD and causes progression of the disease.

Ally number one: Indoxyl Sulphate

The most important uraemic toxin, indoxyl sulphate (see Uraemic toxins), suppresses the synthesis of α-klotho, limiting the ability of FGF-23 to reduce phosphate in the blood and causing CKD to progress.

Indoxyl sulphate is a product of protein digestion. Its precursor, indole, forms when bacteria in the intestines digest proteins. Indole is absorbed from the intestines into the blood and converted to indoxyl sulphate in the liver. This needs to be excreted by the kidneys. Indoxyl sulphate in the blood rises with declining renal function in CKD, because the kidneys are no longer able to adequately excrete this renal toxin. Furthermore it directly damages the kidneys. Indoxyl sulphate is toxic to the kidneys and is also “uraemic toxin”. The higher the level of indoxyl sulphate in the blood, the greater is its toxicity in the cat’s body, especially the kidneys. Indoxyl sulphate accelerates renal decline via various mechanisms. An increase in indoxyl sulphate is therefore associated with increased mortality in CKD. Among other things, indoxyl sulphate also has a negative influence on calcium and, above all, phosphate levels in the blood.

Indoxyl sulphate suppresses the positive effect of FGF-23

FGF-23 and indoxyl sulphate are related to the severity of CKD. This relationship in CKD in humans is well established, but was first confirmed in cats by a recent study by Liao et al. (2019).

There is a linear relationship between FGF-23 and indoxyl sulphate levels. In other words, elevated FGF-23 is associated with correspondingly elevated indoxyl sulphate. At same , the levels of phosphate in the blood of cats also increases. This can be explained by the fact that hyperphosphataemia promotes FGF-23 synthesis, and this leads, via various mechanisms (for example, via calcitriolCalcitriol is the active form of vitamin D3. It is synthesised in the kidney from vitamin D. It is independently activated by three factors: increased parathyroid hormone levels, reduced calcium levels or indirectly via reduced phosphate levels. Calcitriol acts on four organs: 1) Bones: It...), to a reduction in phosphate levels. Elevated blood phosphate levels trigger a feedback and activate mechanisms such as FGF-23 to lower phosphate levels once again. FGF-23, thus, controls phosphate fluctuations in the blood. In order to do so, however, and lower blood phosphate, FGF-23 requires an additional factor: co-factor α-klotho. Consequently, if blood phosphate levels rise FGF-23 levels will also automatically rise. This explains why phosphate and FGF-23 blood levels are directly correlated.

Indoxyl sulphate leads to secondary hyperparathyroidism and increased phosphate levels

On the other hand, a rise in indoxyl sulphate is related to a decline in renal function, which also leads to hyperphosphataemia, because less phosphate and indoxyl sulphate can be excreted via the kidneys. Reduced excretion of indoxyl sulphate and phosphate causes their concentrations in the blood to rise. Elevated blood levels of indoxyl sulphate and phosphate are, thus, biomarkers for reduced renal filtration.

In addition, indoxyl sulphate is causally related to the increase in phosphate levels. Indoxyl sulphate appears to be a potential factor in the secondary hyperparathyroidismDurch die bestehende Hypokalzämie (erniedrigter Kalzium-Blutspiegel) bei der chronischen Nierenerkrankung, aber auch bei Leber- oder Darmerkrankungen kann es zu einer unkontrollierten Produktion von Parathormon (PTH) in der Nebenschilddrüse kommen.... of CKD, which leads to a significant worsening of the disease. Indoxyl sulphate’s negative effect on the co-factor α-klotho also has a negative effect on the ability of FGF-23 to reduce phosphate, as explained above. As a result, FGF-23 is unable to compensate increased blood phosphate. FGF-23 is synthesised in the cells that maintain bone matrix, and these cells are also negatively influenced by indoxyl sulphate. Indoxyl sulphate is involved in other CKD processes, all of which lead to its worsening.

Indoxyl sulphate is responsible for proteinuria

A paper by Liao et al. (2019) has shown that indoxyl sulphate is causally associated with a deterioration in UPC (see urine analyses) and therefore increases protein loss via the urine Indoxyl sulphate leads to defects in the glomerular filtration barrier in the kidneys and also impedes the reabsorption of proteins needed by the body by injuring the relevant cell at these sites. It is, therefore, causally associated with an increase in proteinuriaIncreased protein in urine, leading to loss of protein. Normally, only a very small amount of protein is excreted in the urine. In chronic kidney disease, the amount lost may increase. High blood pressure damages blood vessels in the nephrons making them more permeable and... in cats with kidney disease. Proteinuria is considered to be another important factor in increased mortality in CKD cats, with which indoxyl sulphate is causally linked. In addition, indoxyl sulphate has an effect on CKD progression via other factors, and as a result, it is also considered to be the most important kidney toxin in cats.

Bibliography:

• Liao, Y.-L. / Chou, Ch.-Ch. / Lee, Y.-J. (2018): The association of indoxyl sulfate with fibroblast growth factor-23 in cats with chronic kidney disease; in: Journal of Internal Veterinary Medicine, 33, pp. 686–693.
• Geddes, R. F. / Elliott, J. / Syme, H. M. (2015): Relationship between plasma fibroblast growth factor-23 concentration and survival time in cats with chronic kidney disease; in: Journal of Internal Veterinary Medicine, 29, pp. 1494–1501.
• Cheng, F. P. / Hsieh, M. J. / Chou, C. C. / Hsu, W.L. / Lee, Y. J. (2015): Detection of indoxyl sulfate levels in dogs and cats suffering from naturally occurring kidney diseases; in: The Veterinary Journal 205 (2015), pp. 339–403.
• Elliot, J. (2016): FGF-23: a new player in the regulation of phosphate (2015; reviewed 2016), IRIS International Renal Interest Society
• Finch N.C. / Geddes, R.F. / Syme, H.M. / Elliot, J. (2013): Fibroblast Growth Factor (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats; in: Journal of Vet. Internal Medicine (27), pp. 227–233.
• Geddes, R.F. / Finch N.C. / Elliot, J. / Syme, H.M. (2013): Fibroblast Growth Factor 23 in Feline Chronic Kidney Disease; in: Journal of Vet. Internal Medicine (27), pp. 234–241.