Hypercalcemia in chronic kidney disease (2018)

Henk Van den Broek, Department of Comparative Biomedical Sciences, Royal Veterinary College, London UK NW1 0TU (hvandenbroek@rvc.ac.uk)

The kidneys play a central role in calcium homeostasis, so unsurprisingly disorders of calcium have been associated with chronic kidney disease (CKD) in dogs and cats. Hypercalcemia based on serum total calcium (total hypercalcemia) was observed in 9-22% of dogs1-3 and in 12-21%4,5 of cats with CKD. In both of these species the occurrence of total hypercalcemia was associated with more severe disease.2,4,6 About half of the serum total calcium concentration consists of hydrated ionized calcium ions, and the other half of protein-bound calcium and a small portion of complexed calcium.7 Whilst the mean total calcium concentration generally does not differ among the different stages of CKD in dogs and cats, mean ionized calcium concentration tends to be lower in animals with IRIS CKD Stage 42,4 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.1-5 Calcium disorders form part of chronic kidney disease-mineral and bone disorder (CKD-MBD), a syndrome consisting of mineral disturbances, bone pathology, and soft tissue calcification.8

Only ionized hypercalcemia is likely to impact health, because the ionized calcium fraction is biologically active.9,10 Hypercalcemia due to CKD is most often not severe and owners may not notice clinical signs.9 Nonetheless, hypercalcemia may worsen signs related to CKD as it further reduces glomerular filtration rate (GFR) and can cause anorexia, polyuria and polydipsia, muscle weakness, and constipation.9,11-13 Hypercalcemia can furthermore contribute to urolithiasis11 and, especially in combination with hyperphosphatemia, to soft tissue calcification.14-16 Calcification of the aorta, gastric wall, kidneys, and paws has been reported in cats with CKD.14,17-20 In men with non-dialysis dependent CKD, increased serum calcium concentrations are associated with increased mortality,21 possibly due to vascular calcification which is an important cause of death in human CKD.22 Higher baseline total calcium concentration was not associated with mortality in cats with CKD,23 but under-diagnosis of ionized hypercalcemia may have affected these results. Therefore, the full effect of hypercalcemia on prognosis in cats with CKD remains to be determined.

Calcium regulation

Serum ionized calcium concentration is regulated by the calcium-sensing receptor and multiple hormones, most importantly parathyroid hormone (PTH) and 1,25(OH)2D3 (calcitriol), via an interplay of these hormones on the physiology of the gut, bone, and kidneys.9,24 Calcitriol stimulates intestinal calcium absorption, whilst PTH increases the extracellular calcium concentration by stimulating tubular calcium reabsorption and osteoclastic bone resorption. Changes in serum calcium concentration can be buffered by storage or release of calcium from bone.9,24 Calcitonin is another hormone involved in calcium regulation, and in contrast to PTH it protects against too high serum ionized calcium concentrations.25 Increases in plasma calcitonin concentration in response to both experimentally-induced and naturally occurring hypercalcemia were observed only in some cats,26,i,ii and it could logically be hypothesized that absence of a calcitonin response would predispose cats to the development of ionized hypercalcemia. However, the importance of calcitonin in calcium homeostasis is debatable in adult mammals.27 Although the plasma concentrations of calcitonin and calcium appeared to change in parallel over time within individual cats that did show a response, this response was heterogeneous between cats.ii Moreover, no clear difference in severity of hypercalcemia was observed between groups of cats that did and did not show an increase in calcitonin in response to hypercalcemia.26,ii Calcitonin therefore only appears to play 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 for the veterinarian as to the cause and effect relationship. Renal dysfunction could result in hypercalcemia through mechanisms such as reduced urinary excretion of calcium or increased bone turnover,28 whilst ionized hypercalcemia could cause a decrease in GFR and predispose to nephrocalcinosis, thus resulting in renal azotemia.12,13 We have recently shown that a diagnosis of CKD is a significant risk factor for the development of hypercalcemia in cats, at least based on total calcium.6 Cats with a diagnosis of azotemic CKD were 4 times more likely to develop total hypercalcemia than non-azotemic cats, suggesting that renal dysfunction, or possibly even some management strategies in feline CKD, contribute to a deranged calcium homeostasis.

The pathophysiology of hypercalcemia in CKD is incompletely understood, but several mechanisms may contribute to hypercalcemia in CKD. In dogs with CKD, increases in the complexed calcium fraction predominantly influence serum total calcium concentration.29 A decline in kidney function could therefore contribute to an increase in calcium-containing ionic complexes, and subsequently to total hypercalcemia in this species. The ionized and complexed calcium fractions are freely filtered at the glomerulus, of which 99% is reabsorbed in the renal tubules.24 Decreased glomerular filtration and increased tubular reabsorption are proposed mechanisms by which CKD may contribute to hypercalcemia.28 The reduction in GFR with CKD may contribute to a positive calcium balance if calcium intake exceeds the renal excretory capacity.28,30,31 Tubular reabsorption of calcium could increase due to sustained increases in PTH or inactivating mutations in the calcium-sensing receptor.28 Single nucleotide polymorphisms of the calcium-sensing receptor have been identified in cats,32, and could possibly contribute to increased calcium reabsorption.33 Secondary renal hyperparathyroidism occurs in cats and dogs with CKD,3,4 but hypercalcemia in cats with CKD appears PTH-independent, and physiologically appropriate decreases in plasma PTH concentration in response to hypercalcemia were generally observed in cats.6,11,34

Parathyroid hormone stimulates bone resorption,35 and decreased bone mineral density has been observed in cats and dogs with CKD.36,37 Bone tissue is the most important storage site of calcium in the body, and incapacity of bone to store calcium or increased release of calcium from bone could lead to hypercalcemia.28 Metabolic acidosis is found with increasing frequency as renal function declines,38 and has also been documented to stimulate osteoclastic bone resorption,39 releasing calcium carbonate into the circulation.40 An increased requirement for skeletal buffering of acid could therefore be related to hypercalcemia. Metabolic acidosis is associated with increased urinary calcium excretion in dogs,41,42 but serum ionized calcium concentration does not appear to be affected.43 However, ionized hypercalcemia could develop if renal calcium excretion is impaired.

Do renal diets cause hypercalcemia in cats?

There is debate as to whether clinical renal diets contribute to the development of hypercalcemia in cats. These diets are the mainstay in the management of CKD in cats and dogs and their beneficial effects on quality of life, progression and survival has been proven by multiple studies.34,44-47 Although hypercalcemia and CKD have been diagnosed concurrently (in cats yet to be fed a clinical renal diet),4 hypercalcemia has also been reported to develop in some cats relatively soon after prescription of a clinical renal diet.6,34 In a retrospective study we observed the development of total hypercalcemia in 60 of 191 cats at a median of 175 days after diagnosis of azotemic CKD.6 Although for all cats in that study transition onto a renal diet was advised, no information was available on what owners actually fed these cats. In a smaller prospective study, 2 of 15 cats developed ionized hypercalcemia within 6 months after transition onto a clinical renal diet, and withdrawal of the diet restored normocalcaemia in both cases.34 Clinical renal diets most importantly are restricted in phosphate and protein, but these diets also have lower sodium content, higher potassium content, and alkalinizing properties.48 All these factors could affect calcium homeostasis. Low dietary phosphate or a higher dietary calcium to phosphorus ratio could possibly lead to greater intestinal calcium absorption,16,49 and a positive relationship between intake of purified or hydrolyzed protein and urinary calcium excretion has been identified in humans.50-53 Thus, the lower protein content of renal diets possibly contributes to a decrease in renal calcium excretion. Potassium is supplemented in renal diets, and, depending on its accompanying bicarbonate generating organic anion, reduces urinary calcium excretion.54 Sodium, by contrast, stimulates urinary calcium excretion,55 but is reduced in renal diets. Alkali ingestion possibly contributes to bicarbonate-induced increases in tubular calcium reabsorption.42,56 Therefore, the above characteristics of clinical renal diets (although dependent on the exact formulation) could theoretically all contribute to an increased serum calcium concentration in the cat or dog with CKD.

How to assess calcium status?

Hypercalcemia is diagnosed based on serum calcium concentrations exceeding the upper limit of the reference interval specific for the method used, which usually is a serum total calcium concentration >11.5 mg/dL ( in dogs and >10.5 mg/dL in cats, or an ionized calcium concentration >6 mg/dL in dogs and >5.6 mg/dL in cats.9 Serum total calcium concentration is often used to assess calcium status, but it is best practice to measure the biologically active ionized calcium concentration.7 Total calcium tends to overestimate ionized calcium concentration in dogs with CKD,1 a discordance probably caused by an increase in the complexed calcium fraction due to reduced GFR, resulting in overestimation of true (ionized) hypercalcemia. In contrast, total calcium underestimates the ionized calcium concentration in cats,5,6 a discrepancy probably influenced by acid-base status. It is often stated that cats with CKD typically have total hypercalcemia only, with the ionized calcium concentration within reference interval. 57-59 Although this may be correct in dogs, this assumption seems untrue in cats: the specificity of serum total calcium to detect ionized hypercalcemia in cats with CKD is close to 100%, and almost all cats with total hypercalcemia will have a concurrent ionized hypercalcemia.5,6 The sensitivity, however, is low and (true) ionized hypercalcemia will be under diagnosed in cats when only total calcium is measured. Serum ionized calcium should therefore be measured to allow a correct diagnosis and adequate management in both cats and dogs.

What to do when hypercalcemia is identified?

Unfortunately, the evidence-base for management of hypercalcemia in animals with CKD is small. When persistent and asymptomatic ionized hypercalcemia is identified in a well-hydrated animal, causes of hypercalcemia unrelated to CKD should be investigated. This is particularly true in cats, where CKD is highly prevalent and therefore a common comorbidity.60 In a previous publication on total hypercalcemia in cats, 6 of 33 azotemic hypercalcemic cats had concurrent neoplastic disease.61 Neoplasia is the most common diagnosis in dogs with ionized hypercalcemia, followed by CKD.62 Therefore, thoracic and abdominal radiographs, and abdominal ultrasound should be performed to assess the presence of neoplastic disease. Hypercalcemia in cats is most often of unknown cause (ie. idiopathic hypercalcemia),11 and it is unclear what role pathophysiological mechanisms resulting in idiopathic hypercalcemia play in the development of hypercalcemia in cats with CKD.

Some medications used in the management of CKD-MBD have been associated with hypercalcemia and should be discontinued if this is identified. The use of aluminium-containing phosphate binders has been associated with low bone turnover and hypercalcemia in human CKD patients.63 Use of calcium-containing phosphate binders16,64,65 or vitamin D analogues or metabolites66 also resulted in hypercalcemia in humans with CKD. Both increase the intake of calcium, which could then exceed the impaired capacity of the kidneys to excrete calcium. Therefore, monitoring of serum ionized calcium is recommended if these drugs are used.48 The use of calcitriol is not recommended in cats with CKD.48,67 In dogs, low doses of calcitriol have been shown to prolong survival time in IRIS CKD Stage 3 and 4,68 and hypercalcemia is uncommon.9,68

A diet change is the first step advised for management of cats with mild hypercalcemia.59 When persistent hypercalcemia occurs or is worsening in a cat fed a renal diet, and no other underlying cause has been identified, it is advisable to discontinue feeding 100% renal diet. Either the proportion of renal diet fed on a daily basis could be reduced, or renal diet could be stopped completely. A dietary transition could then be made to a diet less stringently phosphate restricted, such as a senior diet, or to a calcium oxalate prevention diet, which is restricted in calcium. Serum calcium and phosphate concentrations should subsequently be monitored to assess the effect of any dietary change: serum ionized calcium concentration should decrease and phosphate concentration should remain within the IRIS stage-specific target range. One should be aware that hypercalcemia associated with CKD is rarely severe and its prognostic implications largely unknown, whilst strong evidence exists for the beneficial effects of feeding a renal diet to animals with CKD.34,44-47 Therefore, this treatment strategy requires close follow-up and should be clearly discussed with the pet owner.

If serum ionized calcium concentration has not improved 6 weeks after diet change, treatment with specific calcium lowering medications such as bisphosphonates (PO alendronate, IV pamidronate) or prednisolone could be instigated. Bisphosphonates as a treatment option for hypercalcemia have only been examined in few animals, but appear safe and reasonably effective in lowering serum calcium concentrations, although hypercalcemia may reoccur after treatment is stopped.69,70 Promoting calciuresis by intravenous fluid therapy together with furosemide administration could lower serum calcium in the emergency setting, although this is unlikely to be necessary with CKD-related hypercalcemia.

Conclusion

In summary, 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, and total calcium should not be relied on. Multiple mechanisms by which CKD could cause hypercalcemia have been proposed, including reduced urinary excretion of calcium and metabolic acidosis, but underlying causes other than CKD, most importantly neoplasia, should be ruled out. The first treatment option is often a diet change, but the evidence-base for management of hypercalcemia is small.

Flow chart for management of hypercalcemia in cats with CKD and mild/asymptomatic hypercalcemia.

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iManiaki E, Pineda C, Dunbar Z, Finch N. Calcitonin response to naturally occurring hypercalcaemia in cats. J Small Anim Pract 2016; 57(Suppl. 1): 32-33 (abstract).

iiVan den Broek DHN, Geddes RF, Williams TL, Chang Y-M, Jepson RE, Elliott J. Calcitonin response to naturally occurring ionized hypercalcemia in cats with chronic kidney disease. J Vet Intern Med 2018 (accepted for publication).

iiiGeddes RF, Forcada Y, Catchpole B, Elliott J, Syme HM. Eight novel polymorphisms identified in the feline calcium sensing receptor in cats with varying plasma ionised calcium concentrations. J Vet Intern Med 2013; 27: 687 (abstract).

Further reading

Syme HM (2007) Polyuria and polydipsia. In“BSAVA Manual of Canine and Feline Nephrology and Urology” 2nd edn, eds J Elliott and GF Grauer, pp 8-25.

Wamsley H and Alleman R (2007) In“BSAVA Manual of Canine and Feline Nephrology and Urology” 2nd edn, eds J Elliott and GF Grauer, pp 79-86.