Phosphate and CKD

Phosphate plays a special role in CKD cats. The kidneys lose their ability to excrete and regulate phosphate due to the decline in renal performance. Consequently, an excess of phosphate is accumulated in the blood, resulting in elevated phosphate levels. The resulting hyperphosphataemia (= plasma phosphate levels above the normal range) is the best known cause of disease progression, but is also a consequence of CKD. In cats with CKD, hyperphosphataemia increases mortality.

The derailment of the phosphate metabolism is initiated at an early stage. Compensatory mechanisms are involved, which extend via the parathyroid gland (release of parathyroid hormone = PTH), bones (breakdown of calcium-phosphate from the bone and release of FGF-23) and kidneys to the intestine (bone-kidney-gut axis). In individuals with chronic kidney disease (CKD), these mechanisms are altered to a greater extent, thereby further fuelling the disease process. This results in secondary hyperparathyroidism (SHPT), a hyperfunction of the parathyroid gland that leads to excessive production of parathyroid hormone. Parathyroid hormone in turn leads to massive bone loss – mineral and bone disorder (MBD) – in which excessive amounts of calcium and phosphate are released from the bone into the blood, demineralising the bone. The resulting excess of phosphate and calcium leads to calcifications in soft tissues such as the kidneys. The process of renal calcification results in a further decline in the number of functional nephrons. This subsequently impairs the kidney’s performance and ultimately leads to a vicious circle.

The kidneys play a pivotal role in regulating phosphate metabolism

The kidneys are the primary excretory organ for phosphate. It is therefore the kidneys’ task to excrete excess phosphate and also to regulate phosphate levels. Phosphate excretion and regulation occurs via nephrons, which are functional units consisting of two parts: the filter unit with the glomerulus, in which calcium and phosphate are passively filtered out of the blood in addition to waste products and other minerals dissolved in a high amount of water. This produces the first urine as filtrate.

In the second part of the nephron, the tubular system, the filtrate is then further modified by the recovery of important components, including water, sugar (glucose) and also calcium and phosphate. Fine regulation of the phosphate blood level thus takes place in the tubular system. Up to 90% of the filtered phosphate can be recovered here.

Hormones such as parathyroid hormone and FGF-23 (fibroblast growth factor-23) are involved in the recovery of phosphate from the tubular system and influence the amount that is recovered. Anything that is not recovered is excreted. A reduction in the recovery of phosphate in the tubular system stimulated by parathyroid hormone and FGF-23 can contribute to a significant increase in phosphate excretion. In Chronic Kidney Disease (CKD), these two hormones sustain the phosphate blood level at normal levels for an extensive period (until only approximately 20% of the kidney tissue remains functional). However, this is at the cost of increased levels of these substances being present in the blood, which in turn can give rise to further issues, such as secondary hyperparathyroidism (SHPT).

Furthermore, the kidney tissue is responsible for the production of calcitriol, the active form of vitamin D3. Calcitriol ensures that more phosphate is absorbed from the chyme into the blood by increasing the necessary transport systems. Calcitriol also ensures an increased serum calcium level by increasing the absorption of calcium from the intestine and increasing the recovery of filtered calcium in the tubular systems of the nephrons. The effect of calcitriol is designed to provide minerals for the formation of bone. Another crucial function of calcitriol is to inhibit parathyroid hormone production by the parathyroid gland, which is responsible for bone resorption.

Vicious circle of hyperphosphataemia

The vicious circle commences with a reduction in kidney performance, which subsequently leads to a further reduction in kidney performance, accompanied by a progressive loss of functional nephrons. As mineral and bone metabolism are directly related to the kidneys, both are derailed when the kidneys lose their performance due to their disease.

Kidney performance decreases due to loss of functional nephrons

Kidney performance decreases due to loss of functional nephrons

If kidney performance decreases, this means that less phosphate can be filtered out in the nephrons. As a result, excess phosphate builds up in the blood, as the kidneys are the main excretory organs for phosphate. This leads to hyperphosphataemia. Concurrently, the kidneys are no longer capable of producing calcitriol, a hormone that plays a pivotal role in regulating mineral and bone metabolism. In the event of a significant reduction in calcitriol production as a consequence of CKD, the plasma calcium level will decline, resulting in a state of hypocalcaemia. This is accompanied by an elevated phosphate level, which in turn stimulates the secretion of parathyroid hormone.

Parathyroid hormone release due to calcitriol deficiency, hypocalcaemia & hyperphosphataemia

Parathyroid hormone release due to calcitriol deficiency, hypocalcaemia & hyperphosphataemia

As calcitriol also precipitates as an antagonist of parathyroid hormone, the parathyroid gland overproduces and releases parathyroid hormone. The calcitriol deficiency and hyperphosphataemia result in secondary hyperparathyroidism (= SHPT). As a result, parathyroid hormone breaks down bone unhindered, which is referred to as mineral & bone disorder in connection with CKD ( = MBD).

Bone loss & calcification of the kidneys

Calcium and phosphate are released from bone as a result of bone resorption caused by parathyroid hormone. Both minerals are stored in bone as calcium phosphate. Therefore, the breakdown of bone substance always results in the release of phosphate. When bone is massively depleted by the presence of SHPT, the blood levels of calcium and phosphate rise. The body cannot excrete the excess phosphate and deposits it as calcium phosphate in the soft tissues. This leads to calcification of the heart, blood vessels, skin, muscles, paws and kidneys. Kidney calcification (=renal calcinosis) leads to the death of more and more functioning nephrons, further reducing kidney performance.

Phosphate metabolism in detail

The phosphate pathway in cats consists of four main steps from absorption to excretion. In addition to the intestine, the parathyroid gland, bones and kidneys are also involved in phosphate metabolism.

Cats cannot produce phosphate themselves, so they have to ingest phosphate with their food. As cats are obligate carnivores, they also consume a lot of phosphate with animal proteins. Processed food also contains additives that serve as excipients and/or flavour enhancers and may contain phosphate (e.g. sodium diphosphate and other diphosphates). Phosphate must be ingested in a very specific ratio to calcium.

About 80% of the phosphate in the feed is absorbed. The remainder is excreted in the faeces. From the intestine, phosphate is transferred to the blood by two different routes.

One is active, via a transcellular system, i.e. through the cells. This system depends on the number of appropriate transport systems (NaPi2b receptors). Calcitriol increases the number of these transport systems in the intestine so that more phosphate can be absorbed. The second is the paracellular pathway, i.e. between cells. This is a passive pathway. It depends on the strength of the connection between the cells.

There is an equilibrium between calcium and phosphate. Both blood levels are finely regulated. Calcium and phosphate are stored in bones and teeth as their “building material” (apatite) and provide bone stability and strength. Bones are constantly being built up and broken down and can therefore influence blood levels of calcium and phosphate. Bones are the largest reservoir and buffer for calcium and phosphate. Bones and teeth together store about 99% of the body’s calcium and 85% of its phosphate.

Several hormones are involved in bone formation and breakdown. In general, calcitriol ensures that the bones have enough minerals (calcium and phosphate) for bone formation.

As bone is broken down, parathyroid hormone from the parathyroid gland causes the serum calcium level to rise. Phosphate is always released as part of this process. Under the influence of parathyroid hormone, excess phosphate is increasingly excreted by the kidneys.

In addition to parathyroid hormone, the bone hormone FGF-23 is also a cause of increased phosphate excretion in the kidneys. FGF-23 also acts by inhibiting the phosphate transport systems for reabsorption in the tubular system. FGF-23 is activated when phosphate metabolism is out of balance and phosphate levels are too high.

In addition, there is also an interaction between the three hormones. Calcitriol reduces parathyroid hormone production. Parathyroid hormone promotes calcitriol production. FGF-23 inhibits both calcitriol and parathyroid hormone production and PTH release. FGF-23 lowers blood levels of both calcium and phosphate by inhibiting parathyroid hormone, thereby reducing its influence on the release of calcium and phosphate from bone. Furthermore, FGF-23 increases renal phosphate excretion by reducing its retention and simultaneously reduces blood calcium levels and intestinal phosphate absorption by reducing calcitriol production.

Calcitonin from the thyroid also plays an important role in calcium metabolism. It lowers calcium levels by promoting its integration into the bones.

In the filtration apparatus of the nephrons, the glomerulus, phosphate is passively filtered out along with water, urinary substances, other minerals and sugar (glucose). This filtrate forms the primary urine, which is further modified and reduced in the subsequent tubular system. What is important for the body is recovered in the tube system. There are special transport systems for this (e.g. for glucose, e.g. SGLT-1 and SGLT-2 receptors). Up to 90% of the filtered phosphate can be recovered via the phosphate transport systems (NaPi2a and NaPi2b). Parathyroid hormone and FGF-23 act on these transport systems. If the concentration of these two hormones increases, the phosphate transport systems for the retention of phosphate are inhibited and more phosphate is excreted in the urine.

Reducing this retention is a huge opportunity to lower blood phosphate levels. Therefore, elevated phosphate levels are rarely detected in the early stages of CKD. This compensation by FGF-23 and parathyroid hormone can be maintained until less than 20% of the kidney tissue is functional. Hyperphosphataemia then occurs: A CKD-damaged kidney increasingly loses functional kidney tissue and thus nephrons. As a result, there are no longer enough functional filter units to excrete sufficient phosphate. At the same time, parathyroid hormone and FGF-23 no longer act on damaged nephron tubular systems. Both lead to the fact that not enough phosphate can be excreted and the phosphate blood concentration increases further.

Symptoms of hyperphosphataemia

  • Teeth grinding
  • Trembling
  • Eating cat litter
  • Impaired movement (for example weakness of the hind legs)
  • Plantigrade gait: Cats walk on their hocks. This looks like a “rabbit gait”. This occurs due to nerve damage caused by high phosphate levels, but is reversible. This means that the symptoms can be improved if the phosphate level is lowered.

More in-depth knowledge

Further information about the above-mentioned contents, which will shed more light on them (therefore, there may be some redundancies).

FGF-23

FGF-23 is a phosphate-lowering hormone. FGF-23 stands for Fibroblast Growth Factor 23. The hormone is produced by bone cells when phosphate metabolism is disturbed or calcitriol and/or parathyroid hormone are elevated in the blood. FGF-23 increases phosphate excretion in the kidneys by reducing the retention of phosphate in the tubular system. Like parathyroid hormone, it also inhibits the phosphate transport systems (NaPi2a & NaPi2c) in the tubular system, which are responsible for the retention of phosphate from the primary urine. As a result, more phosphate is excreted, which lowers the phosphate level in the blood.

FGF-23 also reduces parathyroid hormone and thus the release of phosphate and calcium from the bone. In addition, FGF-23 inhibits the formation of calcitriol, which lowers the blood calcium level. In later stages of chronic kidney disease in humans, an increased blood level of FGF-23 leads to secondary hyperparathyroidism (SHPT) via the reduction of calcitriol and thus to excessive bone resorption by parathyroid hormone with the resulting mineral & bone disorder (MBD). The inhibitory effect of fibroblast growth factor 23 (FGF-23) on the production and release of parathyroid hormone decreases with increasing chronic kidney disease (CKD) stage. Conversely, FGF-23 has a preventative effect on bone mineralisation.

If kidney performance decreases, the FGF-23 blood level rises progressively. In the late stages of CKD, FGF-23 is therefore exponentially higher than at the beginning. High FGF-23 levels are already prognostically unfavourable in early IRIS stages. The blood concentration of FGF-23 is increased when the phosphate balance becomes unbalanced. This may already be the case in the very early stages of CKD – even if the phosphate blood concentration is still within the normal range at this time due to the phosphate-excreting effect of FGF-23. In human medicine, FGF-23 is considered a marker for the progression of chronic kidney disease and is also associated with increased mortality in chronic kidney disease due to its diverse pathological properties.

By measuring FGF-23 again as part of the kidney profile blood test, it is possible to diagnose a derailment of the phosphate metabolism at a very early stage so that phosphate can then be reduced. If the phosphate level in the blood falls, the FGF-23 blood concentration also falls.

Effects of CKD on the blood levels of phosphate and calcium

Damage to the kidneys has two main consequences:

  1. On the one hand, the phosphate blood level rises because not enough phosphate is excreted. Hyperphosphataemia occurs because there are too few functioning filter units available to filter out phosphate. This occurs in particular when there is less than 20% kidney function. Up to this stage, parathyroid hormone and FGF-23 can keep the blood level in the upper normal range by massively increasing their concentrations in the blood (with the development of SHPT) via increased phosphate excretion in the kidneys.
  2. Secondly, the blood calcium level falls because the damaged kidneys are no longer able to produce sufficient calcitriol. In addition, calcitriol is blocked by the increase in FGF-23 (see point 1). The calcium level drops and the balance between phosphate and calcium is disturbed. This leads to an activation of parathyroid hormone, which breaks down the bone unhindered (without a stop signal from calcitriol, because too little of this hormone is produced in CKD) in order to increase the calcium level. This automatically increases the phosphate level. However, as the excess phosphate cannot be excreted (see point 1), the imbalance between phosphate and calcium remains, so that parathyroid hormone and FGF-23 continue to be released.

Physiological regulation of parathyroid hormone (PTH)

Parathyroid hormone is activated to increase the calcium level in the blood. It has three effects:

  1. It leads to the breakdown of bone substance and thus releases calcium and subsequently also phosphate from the bone (parathyroid hormone stimulates osteoclasts, which are cells that break down bone).
  2. It causes the formation of calcitriol in the kidneys, so that calcium is increasingly absorbed from the intestine into the blood and recovered again in the tubular systems of the kidneys.
  3. It causes the kidneys to excrete more phosphate. This is necessary because phosphate is also released when bones are broken down and otherwise calcium phosphate can precipitate in organs. In the physiological state, the effect of parathyroid hormone on the phosphate blood level is balanced by the release of phosphate from the bones and increased phosphate excretion in the kidneys.

Effects of parathyroid hormone in CKD

In CKD, however, this effect of parathyroid hormone has changed, as the diseased kidneys (points 2 & 3) no longer excrete sufficient phosphate and produce calcitriol. As a result, the remaining effect of parathyroid hormone on bone resorption is limited. Due to the lack of inhibition by calcitriol and the existing imbalance between phosphate (due to hyperphosphataemia) and calcium, the production and release of parathyroid hormone in the parathyroid glands is excessive, resulting in secondary hyperparathyroidism (= SHPT).

Secondary hyperparathyroidism (SHPT) & metabolic bone disease

The reduced kidney function leads to excessive parathyroid hormone production and release from the parathyroid gland. This is known as hyperparathyroidism. “Secondary” because it is caused by the diseased kidneys. This SHPT occurs due to reduced calcitriol production, which usually inhibits the production and release of parathyroid hormone. In addition, a reduced calcitriol level causes the blood calcium level to fall. A falling calcium level is a start signal for the parathyroid gland. As the phosphate concentration in the plasma rises at the same time, the calcium-phosphorus ratio becomes unbalanced, which also stimulates the parathyroid gland to produce and release parathyroid hormone.

FGF-23 is released when the phosphate concentration in the serum rises in order to increase phosphate excretion in the kidneys and thereby reduce the blood level. At the same time, FGF-23 causes an inhibition of calcitriol. In human medicine, this is regarded as the starting signal for the onset of SHPT in the later stages of chronic kidney disease.

Parathyroid hormone causes the release of calcium and phosphate from the bone. Both minerals ensure stability in the bone and, as calcium phosphate, represent the building substance of the bone. If the bone is continuously degraded excessively due to an increased parathyroid hormone concentration in the blood, the result is metabolic bone disease, known as Mineral & Bone Disorder (MBD).

The calcium and phosphate concentrations in the blood rise excessively due to bone resorption. As the kidneys cannot excrete phosphate sufficiently, it is deposited as calcium phosphate in soft tissue, leading to calcification in vessels, skin, muscles and also the renal vessels and kidneys. Renal calcification in turn leads to the further destruction of nephrons and thus to the progression of CKD.

*Blood value, blood concentration, blood level and generally -value, plasma concentration, plasma level or serum concentration, serum level are used synonymously.