The kidneys play a central role in maintaining calcium and phosphate blood levels. Calcium and phosphate are in balance. In chronic kidney disease (CKD), this balance can be severely disturbed. Not only is there an accumulation of phosphate in the blood (hyperphosphataemiaIncreased phosphate in the blood.) (see “The devil’s in the “P”“) due to the retention of phosphates that are not excreted. HypercalcaemiaAbnormal increase in blood calcium due to a disturbance of calcium-phosphate balance. It can occur in chronic kidney disease as a consequence of excessive parathyroid hormone synthesis and subsequent release of calcium from bones (in bone resorption). Elevated calcium levels are also associated with bone..., i.e. an excess of calcium in the blood, can also occur with CKD.
Hypercalcaemia was observed in about 20% of CKD cats, which was associated with severe disease, such as soft tissue calcification (and thus renal calcification), and bone disorders.
Renal calcifications lead to a further worsening of CKD because more nephronsNephrone sind die Filtereinheiten der Nieren.... are destroyed.
One must differentiate between so-called ionised, i.e. unbound, calcium (about one half), protein-bound calcium (about the other half) and complexed calcium (the smallest part). Only ionised hypercalcaemia is likely to affect health, as the ionised calcium fraction is biologically active.
In CKD, the total blood levels of calcium do not differ within the four IRIS stages. However, the ionised fraction decreases with increasing stage. Nevertheless, about 30% of CKD cats develop hypercalcaemia based on the ionised fraction.
Hypercalcaemia can exacerbate symptoms associated with CKD such as refusing to eat, drinking a lot (polydipsiaExcessive thirst due to illness, leading to excessive production of urine (polyuria)....), urinating a lot (polyuriaExcessive production of urine, potentially due to kidney failure....), muscle weakness or constipation. In addition, kidney performance is reduced and stone formation may occur with hypercalcaemia.
In people with chronic kidney disease, hypercalcaemia was associated with an increased mortality rate. According to the authors, this is attributed to vascular calcification. This correlation has not yet been found in CKD cats.
Calcium regulation
The concentration of ionised calcium in the serum is regulated by several hormones, especially 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) and 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... (active vit. D).
Calcium levels are precisely regulated by the interplay of these hormones. The two hormones have different effects on calcium absorption in the intestine, the breakdown or build-up of calcium in the bones and via kidney excretion.
Calcium is predominantly present in the bones. Changes in the calcium concentration in the blood can be buffered by accumulating (building up bone) or releasing (breaking down bone) calcium into or out of the bones.
PTH increases the calcium level. In the kidneys, PTH promotes the recovery of calcium from the primary urineThe initial urine entering the nephron due to filtration of the blood at renal corpuscles. It is not yet concentrated and does not contain any proteins.... ( significantly limited in CKD) and, especially in the bones, the breakdown of bone substance. Calcium phosphate is broken down from the bone, so that calcium is always increased together with phosphate. However, the phosphate blood level is regulated by the promotion of kidney excretion by PTH. This no longer takes place in CKD, because kidney function is reduced. Calcitriol, the antagonist of PTH, is also no longer produced sufficiently, so that PTH continues to contribute further to bone loss and calcification of the kidney without inhibition.
Calcitriol, unlike PTH, prevents excessive concentrations of ionised calcium from occurring in the blood. If too little calcitriol is produced due to CKD, this can possibly lead to an increased ionised proportion of calcium in the form of hypercalcaemia.
Does renal diet cause hypercalcaemia in cats?
There is some discussion as to whether renal diets contribute to the development of hypercalcaemia in cats. These diets are recommended for the treatment of CKD in cats because they are low in protein and phosphate. This contributes to life extension in cats with CKD. The author reports that some cats developed hypercalcaemia relatively soon after starting a renal diet. This was demonstrated in two studies with a total of almost 200 cats. After discontinuation of the diet, the calcium blood level returned to normal. Kidney diets, as described above, are mainly low in protein and phosphate, usually also have a lower sodium content and a higher potassium content as well as buffer substances. All these factors could negatively influence calcium blood levels.
A low phosphate content in the diet or a higher calcium-phosphorus ratio in the feed could possibly lead to a higher absorption of calcium from the intestine.
A lower protein content in the renal diet may contribute to a reduction in calcium excretion in the kidneys. If less calcium is excreted, this increases the blood calcium level.
Potassium is supplemented in kidney diets and this can reduce calcium excretion in the urine. This also increases the blood level of calcium.
Sodium, on the other hand, stimulates calcium excretion in the urine, but is reduced in renal diets. The intake of buffer substances can stimulate increased calcium absorption from the intestine. Therefore, the ingredients in renal diets could theoretically all contribute to increased blood calcium concentrations in CKD cats.
How is calcium status assessed?
Hypercalcaemia is diagnosed when the blood calcium level exceeds the upper limit of normal, which is > 10.5 mg/dl in cats. Biologically active ionised calcium is elevated at concentrations > 5.6 mg/dl in cats. Usually the total calcium concentration is measured during blood controls. It would make sense to also measure the biologically active ionised calcium. However, almost all cats with hypercalcaemia also have ionised hypercalcaemia. Ionised hypercalcaemia alone is underdiagnosed in cats, especially when total calcium is within the normal range. In CKD cats with normal total calcium levels, it therefore makes sense to also determine the ionised calcium blood level.
What to do if hypercalcaemia is diagnosed?
It must be examined whether the hypercalcaemia occurs in connection with CKD, which is often the case. Hypercalcaemia can also have other causes, especially in CKD cats, which often have many diseases. For example, ionised hypercalcaemia also occurs in association with tumours. Hypercalcaemia in cats can also have unexplained causes or occur as a result of certain medications.
The use of calcium carbonate-based phosphate binders should also be considered in this regard. Hence, these are no longer recommended in humans and cats in later stages of CKD.
Bibliography:
- van den Broek, H. (2022): Hypercalcemia in chronic kidney disease (updated 2022); iris-kidney.com
