Hypercalcemia in Chronic Kidney Disease

Adapted from the IRIS education article by Henk van den Broek, Department of Comparative Biomedical Sciences, Royal Veterinary College, London.

Introduction

The kidneys play a central role in regulating calcium, so it is not surprising that calcium disorders have been associated with chronic kidney disease (CKD) in dogs and cats. Hypercalcemia based on serum total calcium (total hypercalcemia) has been found in 9% to 22% of dogs (references 1 to 3) and 12% to 21% of cats with CKD (references 4 and 5). In both species, total hypercalcemia was associated with more severe disease (references 2, 4, and 6).

About half of the serum total calcium consists of free (ionized) calcium ions, and the other half of protein-bound calcium and a small amount of complexed calcium (reference 7). Although mean total calcium generally does not differ between the stages of CKD in dogs and cats, mean ionized calcium tends to be lower in animals with IRIS CKD Stage 4 (references 2 and 4). Even so, hypercalcemia based on serum ionized calcium (ionized hypercalcemia) has been reported in up to 9% of dogs and 30% of cats with CKD (references 1 to 5). Calcium disorders are part of chronic kidney disease–mineral and bone disorder (CKD-MBD), a syndrome of mineral disturbances, bone pathology, and soft tissue calcification (reference 8).

Why Hypercalcemia Matters

Only ionized hypercalcemia is likely to affect health, because the ionized calcium fraction is the biologically active one (references 9 and 10). Hypercalcemia caused by CKD is usually not severe, and owners may not notice any signs (reference 9). Nonetheless, hypercalcemia may worsen the signs of CKD, because it further reduces the glomerular filtration rate (GFR) and can cause loss of appetite, increased urination and thirst, muscle weakness, and constipation (references 9 and 11 to 13). Hypercalcemia can also contribute to urinary stones (reference 11) and, especially together with hyperphosphatemia, to soft tissue calcification (references 14 to 16). Calcification of the aorta, stomach wall, kidneys, and paws has been reported in cats with CKD (references 14 and 17 to 20).

In men with CKD not requiring dialysis, higher serum calcium is associated with increased mortality (reference 21), possibly because of vascular calcification, which is an important cause of death in human CKD (reference 22). A higher baseline total calcium was not associated with mortality in cats with CKD (reference 23), but under-diagnosis of ionized hypercalcemia may have affected these results. Furthermore, total calcium increasing over time was associated with evidence of progressive CKD in a retrospective study (reference 24). The effect of hypercalcemia on the prognosis of cats with CKD remains to be fully determined in prospective studies.

Calcium Regulation

Serum ionized calcium is regulated by the calcium-sensing receptor and by several hormones, most importantly parathyroid hormone (PTH) and calcitriol (1,25-dihydroxyvitamin D3), acting together on the gut, bone, and kidneys (references 9 and 25). Calcitriol stimulates calcium absorption from the intestine, while PTH raises extracellular calcium by stimulating calcium reabsorption in the kidney tubules and bone resorption by osteoclasts. Changes in serum calcium can be buffered by storing calcium in, or releasing it from, bone (references 9 and 25).

Calcitonin is another hormone involved in calcium regulation, and, in contrast to PTH, it protects against serum ionized calcium becoming too high (reference 26). Increases in plasma calcitonin in response to both experimentally induced and naturally occurring hypercalcemia were seen in only some cats (references 27 and 28, and Maniaki et al., 2016), and it could be hypothesized that cats that lack a calcitonin response are predisposed to ionized hypercalcemia. However, the importance of calcitonin in calcium regulation in adult mammals is debatable (reference 29). Although plasma calcitonin and calcium appeared to change in parallel over time in individual cats that did respond, the response varied between cats (reference 28), and no clear difference in the severity of hypercalcemia was seen between cats that did and did not show an increase in calcitonin (references 27 and 28). Calcitonin therefore appears to play only a minor role in calcium regulation in adult cats.

Does CKD Cause Hypercalcemia?

A concurrent diagnosis of hypercalcemia and azotemia can be a diagnostic challenge, because it is not always clear which is cause and which is effect. Kidney dysfunction could cause hypercalcemia through mechanisms such as reduced urinary excretion of calcium or increased bone turnover (reference 30), while ionized hypercalcemia could reduce GFR and predispose to kidney calcification (nephrocalcinosis), resulting in renal azotemia (references 12 and 13). A diagnosis of CKD has been shown to be a significant risk factor for developing hypercalcemia in cats, at least based on total calcium (reference 6). Cats diagnosed with azotemic CKD were 4 times more likely to develop total hypercalcemia than non-azotemic cats, which suggests that kidney dysfunction, or possibly some management strategies for feline CKD, disturb calcium regulation.

The mechanisms of hypercalcemia in CKD are incompletely understood, but several may contribute. In dogs with CKD, increases in the complexed calcium fraction are the main influence on serum total calcium (reference 31), so declining kidney function could increase calcium-containing ionic complexes and so cause total hypercalcemia in this species. The ionized and complexed calcium fractions are freely filtered at the glomerulus, and 99% is reabsorbed in the renal tubules (reference 25). Reduced glomerular filtration and increased tubular reabsorption are proposed ways in which CKD may contribute to hypercalcemia (reference 30). The reduction in GFR with CKD may lead to a positive calcium balance if calcium intake exceeds the kidneys' capacity to excrete it (references 30, 32, and 33). Tubular reabsorption of calcium could increase because of sustained increases in PTH or because of inactivating mutations in the calcium-sensing receptor (reference 30). Single nucleotide polymorphisms of the calcium-sensing receptor have been identified in cats (reference 34) and could possibly contribute to increased calcium reabsorption (reference 35). Secondary renal hyperparathyroidism occurs in cats and dogs with CKD (references 3 and 4), but hypercalcemia in cats with CKD appears to be independent of PTH, and PTH generally decreased appropriately in response to hypercalcemia in cats (references 6, 11, and 36).

Parathyroid hormone stimulates bone resorption (reference 37), and reduced bone mineral density has been seen in cats and dogs with CKD (references 38 and 39). Bone is the most important storage site for calcium in the body, and an inability of bone to store calcium, or increased release of calcium from bone, could lead to hypercalcemia (reference 30). Metabolic acidosis becomes more common as kidney function declines (reference 40), and it has been shown to stimulate bone resorption by osteoclasts (reference 41), releasing calcium carbonate into the circulation (reference 42). An increased need for the skeleton to buffer acid could therefore be related to hypercalcemia. Metabolic acidosis is associated with increased urinary calcium excretion in dogs (references 43 and 44), but serum ionized calcium does not appear to be affected (reference 45). However, ionized hypercalcemia could develop if the kidneys' excretion of calcium is impaired.

Do Kidney Diets Cause Hypercalcemia in Cats?

There is debate about whether clinical kidney diets contribute to hypercalcemia in cats. These diets are the mainstay of CKD management in cats and dogs, and multiple studies have proven their benefits for quality of life, progression, and survival (references 36 and 46 to 49). Hypercalcemia and CKD have been diagnosed together in cats not yet fed a clinical kidney diet (reference 4), but hypercalcemia has also been reported to develop in some cats relatively soon after a kidney diet was prescribed (references 6 and 36). In one retrospective study, total hypercalcemia developed in 60 of 191 cats at a median of 175 days after the diagnosis of azotemic CKD (reference 6). A kidney diet was recommended for all of these cats, but there was no information on what their owners actually fed them. In a smaller prospective study, 2 of 15 cats developed ionized hypercalcemia within 6 months of starting a clinical kidney diet, and stopping the diet restored normal calcium in both cats (reference 36).

Clinical kidney diets are, most importantly, restricted in phosphate and protein, but they also have a lower sodium content, a higher potassium content, and alkalinizing properties (reference 50), and all of these could affect calcium regulation. A low dietary phosphate or a higher dietary calcium-to-phosphorus ratio could increase the absorption of calcium from the intestine (references 16 and 51), and in people there is a positive relationship between the intake of purified or hydrolyzed protein and urinary calcium excretion (references 52 to 55). The lower protein content of kidney diets may therefore reduce the kidneys' excretion of calcium. Potassium is added to kidney diets and, depending on the bicarbonate-generating organic anion that accompanies it, reduces urinary calcium excretion (reference 56). Sodium, by contrast, increases urinary calcium excretion (reference 57), but it is reduced in kidney diets. Alkali intake may also increase tubular calcium reabsorption through bicarbonate (references 44 and 58). All of these characteristics of clinical kidney diets, depending on the exact formulation, could therefore in theory contribute to a higher serum calcium in cats or dogs with CKD.

How to Assess Calcium Status

Hypercalcemia is diagnosed when serum calcium exceeds the upper limit of the reference interval for the method used. This is usually a serum total calcium above 11.5 mg/dL in dogs or 10.5 mg/dL in cats, or an ionized calcium above 6 mg/dL in dogs or 5.6 mg/dL in cats (reference 9). Serum total calcium is often used to assess calcium status, but it is best practice to measure the biologically active ionized calcium (reference 7).

In dogs with CKD, total calcium tends to overestimate ionized calcium (reference 1), probably because reduced GFR increases the complexed calcium fraction, so true (ionized) hypercalcemia is overestimated. In cats, by contrast, total calcium underestimates ionized calcium (references 5 and 6), a discrepancy probably influenced by acid-base status. It is often said that cats with CKD typically have total hypercalcemia only, with ionized calcium within the reference interval (references 59 to 61). This may be correct in dogs, but it appears to be untrue in cats: in cats with CKD, the specificity of serum total calcium for detecting ionized hypercalcemia is close to 100%, and almost all cats with total hypercalcemia also have ionized hypercalcemia (references 5 and 6). The sensitivity of total calcium is low, however, so ionized hypercalcemia will be under-diagnosed in cats if only total calcium is measured. Serum ionized calcium should therefore be measured to allow a correct diagnosis and appropriate management in both cats and dogs.

What to Do When Hypercalcemia Is Found

Unfortunately, the evidence base for managing hypercalcemia in animals with CKD is small. When persistent ionized hypercalcemia without clinical signs is found in a well-hydrated animal, causes of hypercalcemia unrelated to CKD should be investigated. This is especially true in cats, in which CKD is very common and therefore often present alongside other diseases (reference 62). In one study of total hypercalcemia in cats, 6 of 33 azotemic hypercalcemic cats also had neoplasia (reference 63). Neoplasia is the most common diagnosis in dogs with ionized hypercalcemia, followed by CKD (reference 64). Chest and abdominal radiographs and an abdominal ultrasound should therefore be performed to look for neoplasia. Hypercalcemia in cats is most often of unknown cause (idiopathic hypercalcemia) (reference 11), and it is unclear what role the mechanisms behind idiopathic hypercalcemia play in cats with CKD.

Some medications used to manage CKD-MBD have been associated with hypercalcemia and should be stopped if it is found. Aluminum-containing phosphate binders have been associated with low bone turnover and hypercalcemia in human CKD patients (reference 65). Calcium-containing phosphate binders (references 16, 66, and 67) and vitamin D analogues or metabolites (reference 68) have also caused hypercalcemia in people with CKD, because both increase calcium intake, which can exceed the kidneys' reduced ability to excrete calcium. Serum ionized calcium should therefore be monitored if these drugs are used (reference 50). Calcitriol is not recommended for cats with CKD (references 50 and 69). In dogs, low doses of calcitriol have been shown to prolong survival in IRIS CKD Stages 3 and 4, and hypercalcemia is uncommon (references 9 and 70).

A change of diet is the first recommended step in managing cats with mild hypercalcemia (reference 61). When hypercalcemia persists or worsens in a cat fed a kidney diet and no other cause has been found, it is advisable to stop feeding a diet made up entirely of kidney diet. The proportion of kidney diet fed each day can be reduced, or the kidney diet stopped completely. The cat can then be moved to a diet with less stringent phosphate restriction, such as a senior diet, or to a calcium oxalate prevention diet, which is restricted in calcium. In one retrospective study that followed this approach, feeding a diet with a higher phosphorus content and a lower calcium-to-phosphorus ratio instead of the kidney diet returned ionized calcium to normal in 8 of the 10 cats that had developed hypercalcemia after the kidney diet was introduced (reference 71). Similar findings were reported in a second longitudinal observational study using the same approach (reference 72).

Serum calcium and phosphate should then be monitored to assess the effect of the diet change: serum ionized calcium should decrease, and phosphate should remain within the IRIS target range for the cat's stage. Hypercalcemia associated with CKD is rarely severe and its effect on prognosis is largely unknown, whereas there is strong evidence for the benefits of feeding a kidney diet to animals with CKD (references 36 and 46 to 49). This approach therefore requires close follow-up and should be discussed clearly with the owner.

If serum ionized calcium has not improved 6 weeks after the diet change, specific calcium-lowering medications, such as bisphosphonates (oral alendronate or intravenous pamidronate) or prednisolone, can be started. Bisphosphonates have been studied in only a few animals with hypercalcemia, but they appear safe and reasonably effective at lowering serum calcium, although hypercalcemia may recur after treatment stops (references 73 and 74). In an emergency, increasing calcium excretion with intravenous fluids and furosemide can lower serum calcium, although this is unlikely to be needed for hypercalcemia related to CKD.

Summary of the Approach in Cats With CKD and Mild Hypercalcemia

1. Confirm persistent ionized hypercalcemia in a well-hydrated cat by measuring ionized calcium, not total calcium alone.
2. Look for other causes, especially neoplasia, with chest and abdominal radiographs and an abdominal ultrasound.
3. Stop calcium-containing phosphate binders, aluminum-containing phosphate binders, and vitamin D products.
4. If the cat is eating a kidney diet, reduce the proportion of kidney diet or change to a less phosphate-restricted diet, such as a senior diet or a calcium oxalate prevention diet.
5. Recheck ionized calcium and phosphate, making sure phosphate stays within the IRIS target range for the cat's stage.
6. If ionized calcium has not improved after 6 weeks, consider calcium-lowering medication, such as a bisphosphonate or prednisolone.

Conclusion

Hypercalcemia is commonly associated with CKD in cats and dogs and can be a diagnostic challenge. Calcium status should be assessed by measuring serum ionized calcium rather than relying on total calcium. Several ways in which CKD could cause hypercalcemia have been proposed, including reduced urinary calcium excretion and metabolic acidosis, but causes other than CKD, most importantly neoplasia, should be ruled out. The first treatment option is often a change of diet, for which there is some limited evidence in cats (two case series) when hypercalcemia develops after a clinical kidney diet is introduced.

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Additional abstract cited: Maniaki E, Pineda C, Dunbar Z, Finch N. Calcitonin response to naturally occurring hypercalcaemia in cats. Journal of Small Animal Practice 2016;57(Suppl. 1):32–33 (abstract).