The importance of phosphate in feline chronic kidney disease (CKD) is well established.
Owing to a reduced number of nephrons, insufficient phosphate is excreted in the urine. As a result, blood phosphate levels rise, leading to hyperphosphataemiaIncreased phosphate in the blood. and, via the action of 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... (PTH), to a vicious circle of ongoing destruction of the kidneys. This vicious occurs due to the fine balance between phosphate and calcium in the blood. When the phosphate concentration in the blood rises, the parathyroid gland secretes parathyroid hormone (PTH), which compensates by increasing phosphate excretion. However, PTH is not triggered by increased phosphate in the blood but, rather, by reduced calcium. The kidney itself synthesises 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..., the active form of vitamin D, which, along with PTH, controls the calcium-phosphate balance. However, calcitriol production in CKD is significantly reduced, making it difficult to preserve this balance.
Calcitriol promotes absorption of calcium from the intestines raises blood calcium levels. Reduced calcitriol synthesis decreases calcium absorption from the intestines and, with it, blood calcium levels. This stimulates PTH secretion. The role of PTH is to increase calcium levels and reduce phosphate levels. Calcitriol synthesis is stimulated by parathyroid hormone, calcitriol inhibits PTH release.
In CKD, however, the ability of the kidneys to synthesise calcitriol is impaired. As a consequence, regulation of PTH secretion via calcitriol is impaired in CKD cats, and more PTH is secreted by the parathyroid glands. PTH leads to bone demineralisation: calcium is mobilised from the bones to increase calcium levels. This process also releases phosphate from the bones, raising blood phosphate even further and causing more PTH to be released. In the later stages of CKD, this can result in softening of the s and sometimes of the teeth.
On the other hand, the unchecked release of PTH also causes increased bone resorptionThe re-uptake of substances from tissues, in particular bone, into the blood. It should not be confused with absorption, the initial uptake of substances into the body, for instance from food in the intestines, through the lungs and via the skin. Reabsorption, in contrast, occurs... and elevated calcium levels along with calcification of organs. This includes not only skin, vessels and heart but also the kidneys themselves, leading to further destruction of nephronsNephrone sind die Filtereinheiten der Nieren..... Controlling phosphate blood levels will therefore prolong the life of cats with chronic kidney disease and is an essential component of CKD treatment.
A not so new player on the field: FGF-23
Over the last 15 years, further mediators have been identified that are significantly involved in phosphate metabolism. One of these is fibroblast growth factor-23 (FGF-23), which is produced by bone cells that maintain the bone matrix. Similar to PTH, FGF-23 stimulates the excretion of phosphate. The synthesis and release of FGF-23 is stimulated by elevated phosphate levels and also by elevated calcitriol and PTH. FGF-23 is involved in phosphate balance and also calcitriol regulation. It increases phosphate excretion and inhibits calcitriol synthesis in the kidneys. This requires the co-factor α-klotho. In the parathyroid gland, FGF-23 inhibits PTH synthesis and secretion.
Experiments on mice have demonstrated that FGF-23 deficiency leading to hyperphosphataemia is associated with increased phosphate reabsorption (recovery of phosphate in the kidneys). The mice were also found to have increased calcitriol synthesis and reduced PTH blood concentrations. Administration of gene-technology-derived FGF-23 in mice led, conversely, to hypophosphataemia (reduced phosphate level in the blood) and increased phosphate excretion in the urine. Both experiments suggest that FGF-23 plays an important role in phosphate metabolism.
In addition, FGF-23 can also be regarded as a biomarker for kidney function (as measured by the “glomerular filtration rateThe glomerular filtration rate (GFR) is defined as the volume of fluid that is filtered by the glomeruli of the nephrons of both kidneys per unit of time to produce primary urine. It is, therefore, the chief measure of kidney function. The rate corresponds to...” (GFR)), since it increases when the GFR decreases and FGF-23 needs to be excreted via the kidneys. This means that each of the four IRIS stages is accompanied by increasing concentration in the blood of FGF-23. Likewise, cats with very high phosphate levels (hyperphosphataemia) have higher FGF-23 blood levels than cats with normal phosphate levels at the same IRIS stage.
Allies of mortality
In human medicine, FGF-23 blood levels are directly correlated with mortality in chronic kidney disease patients, and this is also assumed to be the case in CKD cats. FGF-23 blood levels can, therefore, serve as a prognostic biomarker. Elevated blood FGF-23 levels can even be a first indication of CKD, even before the detection of increased 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... and 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... concentrations in the blood. FGF-23 can also be elevated before phosphate levels become elevated, signalling the onset of the disease and the need to control phosphate levels.
The connection between uraemic toxinsToxic, nitrogen-containing urinary substances responsible for uraemia and kidney damage.... and FGF-23 is also intriguing. Indoxyl sulphate is arguably the most important and most harmful uraemic toxin. It needs to be excreted via the kidneys and is, therefore, elevated in the blood in CKD. In addition to directly injuring the kidneys and thus contributing to kidney decline, it also effects phosphate metabolism. By suppressing the synthesis of co-factor α-klotho, required to activate FGF-23, it limits the ability of FGF-23 to reduce phosphate levels.
Bibliography:
- 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.
