Renal Secondary Hyperparathyroidism in Dogs

3 CE CREDITS CE Article

❯❯ Jenefer R. Stillion, DVM Abstract: The parathyroid glands secrete parathyroid hormone (PTH), which is important for main- Cornell University Hospital taining calcium homeostasis. Parathyroid gland hyperplasia and subsequent hyperparathyroid- for Animals ism can occur secondary to chronic renal failure in dogs, resulting in significant alterations in ❯❯ Michelle G. Ritt, DVM, calcium metabolism. Renal secondary hyperparathyroidism is a complex, multifactorial syndrome DACVIM that involves changes in circulating levels of calcium, PTH, phosphorus, and 1,25-dihydroxychole- University of Minnesota calciferol (calcitriol). An increased PTH level can have deleterious effects, including soft tissue College of Veterinary Medicine mineralization, fibrous osteodystrophy, bone marrow suppression, urolithiasis, and neuropathy. Dietary phosphorus restriction, intestinal phosphate binders, and calcitriol supplementation may slow the progression of renal disease and decrease PTH concentrations in animals with secondary hyperparathyroidism; however, the prognosis for these animals is guarded to poor.

he four canine parathyroid glands Importance of Calcium are embedded in the poles of the two The control of calcium metabolism is Tlobes of the thyroid gland, although important because calcium plays an inte- they share no anatomic or physiologic gral role in many physiologic processes. At a Glance connections with the thyroid gland. The Serum calcium must be maintained in main function of the parathyroid glands a narrow range for normal nerve and Importance of Calcium is to maintain calcium metabolism in the muscle function, heart muscle contrac- Page E1 body. In response to decreasing levels of tion, cell membrane stability and linkage, Renal Secondary serum ionized calcium (iCa), chief cells in coagulation, and, to a small degree, struc- Hyperparathyroidism the parathyroid gland secrete parathyroid tural integrity of bones and teeth. Calcium Page E3 hormone (PTH). PTH acts on the bones, in the extracellular fluid helps regulate Causes of Hypercalcemia kidneys, and, indirectly, intestinal mucosa the cellular functions of several organs, in Dogs to elevate the serum calcium level.1,2 including the kidneys, thyroid C cells, Page E5 Patients with parathyroid hyperplasia and parathyroid glands. Calcium ions also Clinical Signs of Chronic and hyperparathyroidism secondary to serve as messengers, conveying signals Renal Failure and Primary chronic renal failure (CRF) have significant from cell surfaces into cells.3 Hyperparathyroidism in Dogs alterations in calcium metabolism2,3 as well Page E6 as changes in circulating levels of PTH, Calcium Distribution Expected Diagnostic Test phosphorus, and 1,25-dihydroxycholecal- Most calcium (99%) is found in bone in Results for the Most Common ciferol (calcitriol). The diagnosis, treatment, the form of hydroxyapatite crystals, which Causes of Hypercalcemia and prevention of renal secondary hyper- contain phosphate, water, and calcium.1,2 Page E7 parathyroidism are important because Intracellular calcium accounts for most Available Oral Phosphate excess PTH may complicate treatment and of the remaining calcium in the body. In Binders and Recommended cause progression of renal disease in dogs. inactive cells, the intracellular iCa level Dosages for Use in Dogs This article reviews the normal physiology is low because most calcium is bound to Page E8 and metabolism of calcium as they relate to protein or contained in the mitochondria the pathogenesis, diagnosis, and treatment or endoplasmic reticulum. As cell activ- of renal secondary hyperparathyroidism. ity increases, so does the intracellular iCa

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level. The smallest pool of calcium in the body cells in response to a low serum iCa level. is the extracellular fluid component, which Increased PTH secretion leads to an increase comprises complexed calcium (bound to phos- in serum concentrations of total calcium and phate, sulfate, bicarbonate, citrate, and lactate), iCa and a decrease in the serum phosphate iCa, and protein-bound calcium. Extracellular concentration. If the serum calcium level is iCa is the most important factor in controlling chronically decreased, such as in animals with QuickNotes the calcium serum concentration.1,2 renal failure or those that are pregnant or lactating, hyperplasia of the parathyroid glands Serum ionized Regulation of Calcium in the Body occurs.3 The enlarged glands are more sensi- calcium, not total Normal calcium homeostasis is maintained tive to small reductions in the calcium level calcium, should be principally by the actions of three hormones: and secrete PTH more efficiently. measured in dogs PTH, calcitriol, and calcitonin (Figure 1). These PTH acts on the kidneys to increase with chronic renal hormones control the movement of calcium the serum calcium level by increasing cal- failure to diag- between the extracellular fluid, gastrointestinal cium reabsorption from the renal proximal nose and monitor tract, kidneys, and bones. Phosphorus is also tubules.1,2 It acts on bone tissue to increase changes in the an important regulator of calcium. calcium resorption from the bone matrix to elevate the serum calcium level, principally calcium level. Parathyroid Hormone by stimulating osteoclasts, which digest bone The serum calcium level is monitored by spe- matrix and increase the calcium ion level in cific membrane calcium receptors on the sur- the matrix fluid. Calcium ions are then trans- face of the chief cells of the parathyroid gland. ported from the bone fluid to the extracellu- PTH is synthesized and secreted by these lar fluid via an extensive membrane system formed by the processes of osteocytes and FIGURE 1 osteoblasts.1,3 PTH indirectly increases intestinal absorption of calcium and phosphorus Increased calcium through the conversion of calcidiol to calcitriol 2 resorption Increased in the proximal renal tubules. calcium absorption Bone Calcitriol Dogs ingest vitamin D (calciferol) in their Intestines food, and it is absorbed from the intestines. Calciferol is hydroxylated in the liver to pro- Calcitonin duce 25-hydroxyvitamin D (calcidiol), which PTH is further hydroxylated to calcitriol in the kidneys.2 In response to hypocalcemia, PTH is secreted from the parathyroid glands and stimulates the synthesis and secretion of calcitriol by the kidneys. Calcitriol acts directly on Kidneys Calcitriol enterocytes to increase intestinal absorption of calcium and phosphorus. In the kidneys, calcitriol increases reabsorption of phosphorus and calcium from the glomerular filtrate. Increased It also exerts negative feedback on the kid- calcium neys to inhibit the production of more calcit- reabsorption riol and on the parathyroid glands to decrease PTH synthesis and secretion when the serum Hormonal regulation of calcium homeostasis. Normal calcium homeosta- calcium level is high.1–3 sis is maintained principally by the actions of parathyroid hormone (PTH), calcitriol, and calcitonin. These hormones control the movement of calcium between Calcitonin the extracellular fluid, gastrointestinal tract, kidneys, and bones. Positive feedback Calcitonin is secreted by the parafollicular (+) is indicated by the solid lines; negative feedback (–) is indicated by the dashed C cells of the thyroid gland in response to line. (Adapted from Polzin DJ, Osborne CA, Ross S. Chronic renal failure. In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine Diseases of increases in serum calcium. It acts on bone the Dog and Cat. 6th ed. St Louis: Elsevier; 2005:1756-1785.) tissue to decrease the serum calcium level by

E2 Compendium: Continuing Education for Veterinarians® | July 2009 | CompendiumVet.com FREE Renal Secondary Hyperparathyroidism in Dogs CE stimulating osteoblasts to increase calcium mal tubules. This deficit precedes the increase absorption and deposition in the skeleton in the serum phosphate level. Extracellular iCa and inhibiting osteoclasts to decrease bone subsequently decreases due to reduced intesti- resorption of calcium.1 In a healthy animal, nal absorption of calcium, which is mediated by the action of calcitonin is less important than calcitriol. Because calcitriol acts directly on the that of PTH for minute-to-minute regulation parathyroid glands to regulate PTH secretion, of serum calcium. However, it is important in a decrease in calcitriol also leads to a lack of growing, pregnant, and lactating animals, in negative feedback and a further increase in the which it protects the bones from excess cal- PTH level. This mechanism may coexist with cium loss.1 decreased renal phosphorus excretion. Other factors that may contribute to the Phosphorus development of hyperparathyroidism in CRF In a healthy animal, PTH acts on the kidneys include alterations in the set point for the to increase renal excretion of phosphate ions response of the parathyroid glands to calcium and reabsorption of serum calcium, thereby and decreased breakdown of PTH by the dis- increasing the serum calcium level.1,2 Decreases eased kidneys.2 in serum phosphate lead to an increase in extracellular calcium.3 Sudden elevations in Chronic Renal Failure and Calcium extracellular phosphate have been shown Unlike primary hyperparathyroidism, in which QuickNotes to directly stimulate PTH secretion in vivo.4 the parathyroid glands function autonomously However, no clinical studies have yet been and lead to a high total serum calcium level Ionized hypercal- done to determine whether acute elevations secondary to increased production of calcit- cemia is relatively in phosphate have an effect on PTH secretion riol and calcium absorption from the gut, total uncommon in dogs in animals with conditions leading to chronic with chronic renal phosphate retention. Dogs fed diets high in FIGURE 2 failure because of phosphorus and low in calcium can develop CRF concurrent hyper- nutritional secondary hyperparathyroidism. phosphatemia and These dogs are typically young and fed a predominantly meat diet.1,3 decreased calcitriol synthesis by the Renal Secondary Hyperparathyroidism kidneys. Parathyroid gland hyperplasia and hyperpara- GFR Nephrons thyroidism can occur secondary to CRF. The accepted explanation of the pathogenesis of this syndrome involves the kidneys’ progressive inability to excrete phosphorus3,5 (Figure Phosphate retention 2). Dogs with CRF have a progressive loss of nephrons and a decreased glomerular filtration rate (GFR). The reduced GFR leads to increases in serum concentrations of substances that are normally filtered from the blood by the kidneys, Calcium including phosphate. As the serum phosphate concentration increases, the iCa level decreases, stimulating the release of PTH. Because the serum phosphate level remains high, the parathyroid glands are chronically stimulated to PTH increase the serum calcium level, leading to parathyroid hyperplasia. The phosphate theory of renal secondary A calcitriol deficit in may also explain renal hyperparathyroidism. With chronic renal dis- 3,5,6 Figure 3 secondary hyperparathyroidism ( ). ease, a decreased glomerular filtration rate G( FR) Along with severe electrolyte abnormalities, a leads to an increased serum phosphate concentra- calcitriol deficit may occur in CRF secondary to tion and a decreased iCa level, which stimulates decreased synthesis from damaged renal proxi- the release of PTH.

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FIGURE 3 renal disease progresses, the iCa concentration may be normal or low. However, ionized hypercalcemia can develop as a consequence CRF of CRF or can contribute to renal azotemia by mineralizing renal tubules (nephrocalcinosis), decreasing GFR, altering renal blood flow, and impairing renal concentrating ability, lead- Number of renal tubular cells ing to polyuria and polydipsia.2,10 Treatment with calcium-containing phosphate binders or calcitriol supplementation can also lead to increased iCa.2 Measurement of total calcium is not a reli- Synthesis of calcitriol able assessment of calcium status in dogs with CRF.11 The measured total calcium level has been shown to correlate poorly with the iCa level. A recent study12 of serum iCa levels in Calcium absorption from the gut Lack of negative feedback dogs with CRF found that measurement of total calcium underestimated hypocalcemia, with 56% of the dogs diagnosed as hypocal- cemic based on iCa levels and only 8% based on total calcium levels. Another study11 of total PTH calcium levels adjusted for albumin concentrations in dogs with CRF showed total calcium to

Calcitriol deficiency and renal secondary hyperparathyroidism. underestimate hypocalcemia and overestimate Calcitriol deficit occurs in chronic renal disease secondary to decreased synthe- hypercalcemia compared with iCa. Because of sis by damaged renal proximal tubules. Extracellular iCa subsequently decreases this variability, iCa, the most physiologically due to reduced intestinal absorption of calcium, which is mediated by calcitriol. relevant form of calcium in the body, should A decrease in calcitriol also leads to a lack of negative feedback and a further be evaluated in dogs with CRF instead of total increase in the PTH level. calcium. In-house blood analyzers are available to measure serum iCa. calcium concentrations in dogs with renal secondary hyperparathyroidism can be normal, Clinical Signs elevated, or low.3 Studies looking at calcium With renal secondary hyperparathyroidism, concentrations in dogs with CRF have mainly serum calcitriol and iCa levels initially return to QuickNotes focused on the total calcium concentration. normal as a result of an increased serum PTH Dogs with renal Hypercalcemia, based on total calcium levels, level. However, they can remain normal only secondary hyper- has been observed in approximately 10% of if PTH secretion remains increased, which has dogs with CRF, and the prevalence appears to deleterious effects on the body. As renal dis- parathyroidism increase with the severity of azotemia.2,7,8 ease progresses, the kidneys synthesize and may present with In contrast to an elevated total calcium secrete less calcitriol and excrete less phos- lameness, patho- level, ionized hypercalcemia is relatively phorus. Hyperphosphatemia and decreased logic fractures, or uncommon in dogs with CRF because of con- calcium absorption from the gut lead to a facial swelling due current hyperphosphatemia and decreased chronically increased PTH level. The resulting to bone demineral- calcitriol synthesis by the kidneys.2,3 Early mobilization of calcium stores can lead to con- ization and fibrous in renal disease, an elevated PTH level can ditions such as fibrous osteodystrophy, bone osteodystrophy of maintain a normal serum phosphate level by marrow suppression, soft tissue mineraliza- increasing the amount of phosphate lost in the tion, urolithiasis, and neuropathy.2 the jaw and long urine. However, as renal disease progresses, Bone demineralization occurs in progressive bones. the kidneys cannot excrete enough phosphate renal disease as osteoclastic activity increases to prevent hyperphosphatemia. Calcitriol syn- to maintain normal calcium and phosphorus thesis also decreases with progressive loss of concentrations. The bones most vulnerable functional nephrons, leading to decreased cal- to demineralization are dental alveolar bone cium absorption from the gut.9 Therefore, as and the cancellous bone of the maxilla and

E4 Compendium: Continuing Education for Veterinarians® | July 2009 | CompendiumVet.com FREE Renal Secondary Hyperparathyroidism in Dogs CE mandible.13 Radiographs may reveal loss of FIGURE 4 the lamina dura around the teeth, decreased bone density, and soft tissue mineralization of the gastric mucosa or other tissues14 (Figure 4). Symmetric swelling of the maxilla and mandible, a soft pliable mandible or “rubber jaw,” pathologic fractures, and bone pain are all suggestive of fibrous osteodystrophies seen with renal failure. Affected dogs may present with lameness or a stiff gait. Because of the higher skeletal metabolic rates in growing animals, young dogs generally develop proliferative bone lesions, whereas general- ized osteodystrophy and rubber jaw are more common in older dogs.13 When the product of serum calcium and phosphate concentrations exceeds 60 to 70 mg/dL, soft tissue mineralization occurs,2,6 predominantly in damaged tissue. In the kidneys, mineralization may cause further deterioration of renal function and Right lateral skull radiograph of a 7-month-old golden retriever with CRF sec- worsen hyperphosphatemia and secondary ondary to renal dysplasia. Note the absence of the lamina dura around the tooth roots (white arrowhead) and thickening of the maxilla (red arrowhead). hyperparathyroidism. A thorough evaluation is necessary to help differentiate hypercalcemic animals with CRF nodular hyperplasia, which may affect more QuickNotes and secondary hyperparathyroidism from those than one gland.3 Secondary hyperparathy- with another cause of hypercalcemia (Box 1). roidism is characterized by diffuse parathy- Dietary phosphorus A complete physical examination, thorough roid gland hyperplasia.3,15 Dogs with primary restriction and the history, complete blood count, urinalysis, tho- hyperparathyroidism may have clinical signs use of phosphate racic radiography, abdominal ultrasonography, similar to those in animals with secondary binders can lower and cervical ultrasonography to evaluate the hyperparathyroidism from other causes, but the serum phos- parathyroid glands are recommended. On their signs are generally subtle or absent com- phate level and, ultrasonography and gross examination of the pared with animals with primary renal failure subsequently, the parathyroid glands, dogs with primary hyper- (Table 1). parathyroidism usually have a solitary ade- parathyroid hor- noma, although they can have carcinoma or Diagnostic Testing mone level, which Serum Ionized Calcium has been shown to Box 1 Measurement of the serum iCa concentration slow the progres- can help distinguish between primary hyper- Causes of Hypercalcemia sion of renal dis- parathyroidism and renal secondary hyperpara- ease and extend the in Dogs thyroidism (Table 2). As previously discussed, life of chronic renal the serum iCa level is usually high with pri- failure patients. Malignancy mary hyperparathyroidism and normal to low ❯ Lymphosarcoma with renal secondary hyperparathyroidism. ❯ Apocrine gland carcinoma of anal sac Changes in blood pH can affect the iCa level. ❯ Other malignancies (rare) An acidic pH increases the amount of iCa in a 2 Hypoadrenocorticism sample; an alkaline pH causes a decrease. For Chronic renal failure in-house analysis, blood should be drawn and Primary hyperparathyroidism analyzed immediately to prevent the changes Hypervitaminosis D in pH that occur as a result of loss of carbon Hyperthyroidism (rare) dioxide. For laboratory analysis, anaerobi- Nutritional secondary hyperparathyroidism cally obtained and stored serum is preferred Granulomatous disease because iCa and pH are more stable in serum than in heparinized or whole blood. Some

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blood analyzers mathematically manipulate remain normal to high in the presence of an the pH value and iCa concentration to yield elevated serum iCa level. In dogs with renal an adjusted value, allowing samples to be secondary hyperparathyroidism, the serum obtained in a routine manner. Because differ- PTH level may be elevated, but serum iCa is ences exist between in-house analyzers, refer- usually normal to low. In general, dogs with ence ranges for an individual analyzer should hypercalcemia not related to parathyroid dis- be established before use.3 ease should have low to normal serum PTH levels.2,16 Serum PTH A recent study17 demonstrated hyperpara- The serum PTH level is one of the most impor- thyroidism secondary to hyperadrenocorticism tant diagnostic aids in dogs suspected of having in dogs. As in dogs with renal secondary parathyroid disease (Table 2). PTH is measured hyperparathyroidism, serum PTH levels were in serum by radioimmunoassay. Most human elevated in these patients, but serum iCa was and veterinary laboratories currently use the normal to low. Therefore, in patients with two-site PTH assay system,3 which depends clinical signs of Cushing’s disease, the adrenal on the production of two polyclonal antibodies and parathyroid glands should be evaluated in that bind to intact PTH. Samples obtained for conjunction with the iCa level. this assay should be stored and shipped frozen to prevent degradation of PTH. Serum collected Serum Parathyroid Hormone-Related Protein with EDTA is adequate.2 Parathyroid hormone-related protein (PTHrP) It is important to evaluate serum PTH rela- is a protein similar to PTH in structure and tive to serum total and iCa concentrations. In sequence. It is found in many types of cells primary hyperparathyroidism, in which PTH (e.g., endocrine, central nervous system, mes- QuickNotes secretion is not suppressed by an increased enchymal, epithelial) and plays a key role in calcium concentration, the PTH level will the development of hypercalcemia associated The serum PTH level is one of the table 1 most important Clinical Signs of Chronic Renal Failure diagnostic aids in and Primary Hyperparathyroidism in Dogs dogs suspected of having parathyroid System Affected Signs of Chronic Renal Failure Signs of Primary Hyperparathyroidism disease. Urinary Polyuria/polydipsia Polyuria/polydipsia Isosthenuria Urinary incontinence Urinary tract infection Dysuria Pollakiuria Hematuria Cystic calculi Neuromuscular Weight loss Listlessness Poor body condition Weakness Lethargy Exercise intolerance Depression Shivering Dehydration Muscle wasting Stiff gait Gastrointestinal Vomiting Inappetence Diarrhea Vomiting Anorexia Constipation Cardiovascular Hypertension —

E6 Compendium: Continuing Education for Veterinarians® | July 2009 | CompendiumVet.com FREE Renal Secondary Hyperparathyroidism in Dogs CE with malignancy.2,3 In a hypercalcemic animal, calcipotriene psoriasis medication, or plants measuring serum PTHrP can help distinguish that contain glycosides of calcitriol can pre between hypercalcemia due to primary hyper- sent with hypercalcemia, hyperphosphatemia, parathyroidism and hypercalcemia of malig- and renal azotemia similar to animals with nancy. Serum PTHrP levels are elevated in secondary hyperparathyroidism.3 However, the animals with hypercalcemia of malignancy and hypercalcemia seen with vitamin D toxicosis is should be undetectable in animals with hyper- usually severe and rapid in onset, often escalat- calcemia due to primary hyperparathyroidism ing within 24 hours after ingestion.2 A history (Table 2). However, this test alone cannot dif- of ingestion or sudden onset of clinical signs, ferentiate between renal secondary hyperpara- such as vomiting, anorexia, tremors, or polyu- thyroidism and hypercalcemia of malignancy ria, can also help differentiate hypervitamino- because animals with renal disease can have sis D from CRF. With vitamin D toxicosis, the increased immunoreactivity to PTHrP frag- PTH level should be normal to low and the ments.3 In a hypercalcemic patient, malignancy serum calcitriol level elevated.3 The serum level is usually diagnosed based on further diagnos- of 25-hydroxyvitamin D (calcidiol), a vitamin D tic tests, such as aspiration of lymph node, liver, metabolite, is elevated in cases of cholecalcif- and spleen tissue; abdominal ultrasonography; erol or ergocalciferol rodenticide ingestion.2 and chest radiography. Therefore, serum assays for PTHrP are rarely indicated and should not Additional Diagnostics be conducted in patients with renal disease. A common cause of elevated serum total calcium is hypoadrenocorticism (Addison’s disease). Serum Calcitriol These animals are often azotemic, hyperphos- Measurement of serum calcitriol can help phatemic, and significantly ill on presentation, distinguish between primary and second- similar to animals with CRF and vitamin D toxi- QuickNotes ary hyperparathyroidism (Table 2). Calcitriol cosis. However, with Addison’s, serum iCa and levels are generally elevated in patients PTH levels are usually normal.3 A diagnosis of Measurement with primary hyperparathyroidism because hypoadrenocorticism should be confirmed or of serum calcitriol of increased calcitriol production. They are ruled out with an ACTH stimulation test. can help distinguish decreased in patients with renal secondary between primary hyperparathyroidism because of decreased Management and secondary renal production of calcitriol. Animals with Phosphorus Restriction Therapy hyperparathyroidism. vitamin D intoxication secondary to ingestion While there is no cure for CRF, the progres- of cholecalciferol or ergocalciferol rodenticide, sion of disease and development of second-

table 2 Expected Diagnostic Test Results for the Most Common Causes of Hypercalcemia

Serum Concentration Primary Chronic Renal Malignancy Vitamin D Measured Hyperparathyroidism Failure Toxicosis

Total calcium ↑ N, ↑, ↓ ↑ ↑ Ionized calcium ↑ N to ↓ ↑ ↑ Phosphorus ↓ ↑ N ↑ Calcitriol ↑ N to ↓ N to ↓ ↑ PTH ↑ ↑ N to ↓ N to ↓ PTHrP Absent Absent to ↑ ↑ Absent

N = normal, ↓ = decreased, ↑ = increased (Adapted from Schenck PA, Chew DJ, Nagode LA, Rosol TJ. Disorders of calcium: hypercalcemia and hypocalcemia. In: DiBartola SP, ed. Fluid, Electrolyte, and Acid- Base Disorders in Small Animal Practice. 3rd ed. St. Louis: WB Saunders; 2006:122-194.)

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ary hyperparathyroidism may be slowed by chloride. It has been shown to reduce hyper- controlling the serum phosphate level. A low- calcemic episodes and subsequent vascular phosphate diet should be instituted in animals and renal calcification in people with CRF with signs of renal failure. Clinical studies compared with calcium-containing phosphate suggest that dietary phosphorus restriction binders.21 There is some concern that the may delay the progression of renal disease by release of chloride ions with phosphate bind- dampening renal secondary hyperparathyroid- ing may create or worsen metabolic acido- ism and preventing renal interstitial mineral- sis, with a subsequent decrease in the serum ization.6 Studies in dogs have shown not only bicarbonate level. Newer forms of sevelamer a decrease in serum phosphate and PTH but contain carbonate instead of chloride to also an increased survival time in animals fed address this concern.22 Studies comparing the phosphorus-restricted diets compared with efficacy of sevelamer and calcium-containing those fed an unrestricted diet.18,19 Progression binders in controlling phosphorus levels have of renal failure may also be slowed, as sug- yielded mixed results.23–25 Sevelamer is a more gested by a stabilized GFR and a lower serum expensive drug and can cause gastrointestinal creatinine concentration, in dogs fed phos- upset.20 Specific clinical trials have yet to be phorus-restricted renal diets.18,19 performed in dogs. In addition to feeding a phosphorus-restricted diet, administration of oral phosphate binders Calcitriol Therapy such as aluminum hydroxide (Amphojel; Wyeth Lowering serum PTH levels in animals with Laboratories, Collegeville, PA), calcium carbonate, CRF is important because it has been sug- or sevelamer hydrochloride (RenaGel; Genzyme, gested that PTH itself may contribute to the Cambridge, MA) can help lower serum phos- progression of renal disease.15 The use of QuickNotes phate levels (Table 3). These drugs indirectly phosphate binders and a reduction in dietary decrease the serum phosphate level by binding phosphorus intake usually lowers but does Lowering serum phosphates in the intestinal tract and prevent- not always normalize an elevated serum PTH PTH levels in ani- ing their absorption. Aluminum hydroxide is a level. In animals with normal serum phos- mals with CRF is better phosphate binder than calcium carbonate phate and normal to low calcium levels, calci- important because in the more acidic environment of the stomach. triol supplementation has been used to further it has been sug- However, in the more alkaline environment of decrease PTH concentrations. Calcitriol works gested that PTH the intestines, calcium carbonate works equally by binding to specific receptors within para- well. Common adverse effects of phosphate thyroid chief cells to block PTH synthesis and itself may con- binders include constipation and nausea. Also, secretion. It may also restore a lower calcium tribute to the pro- hypercalcemia can develop when calcium- set point, which further inhibits PTH secretion gression of renal containing phosphate binders are used. This and prevents or reverses parathyroid gland disease. risk can be minimized by administering these hyperplasia.26 Studies have shown that calcit- agents with a meal to maximize the binding of riol supplementation lowers serum PTH levels calcium to phosphorus and thereby decrease and reduces the severity of secondary hyper- calcium absorption.20 parathyroidism in dogs with CRF.5,26,27 It may Sevelamer hydrochloride is a metal- and cal- also prolong survival time in dogs with stage cium-free polymer resin phosphate binder that III or IV kidney disease.28 works by binding phosphorus in exchange for Calcitriol has been shown to increase serum calcium and phosphorus levels; therefore, nor- table 3 mal serum phosphate and calcium concentra- Available Oral Phosphate Binders and tions should be established before starting Recommended Dosages for Use in Dogs calcitriol therapy.6,27,28 Calcitriol should be used with caution in combination with calcium- Drug Dosage containing phosphate binders because of the increased risk of hypercalcemia. Human dialy- Aluminum hydroxide5 30–90 mg/kg/day PO with food sis patients treated with calcitriol in combina- Calcitriol21,25 2.5 ng/kg PO once daily tion with sevelamer hydrochloride or calcium carbonate have shown equal improvements in 22-Oxacalcitriol23 0.025–0.05 µg/kg PO once daily phosphorus levels and in parathyroid-induced

E8 Compendium: Continuing Education for Veterinarians® | July 2009 | CompendiumVet.com FREE Renal Secondary Hyperparathyroidism in Dogs CE bone disease. However, serum calcium levels Monitoring Response to Treatment increased in patients treated with calcitriol and PTH, serum calcium, phosphorus, and creati- calcium carbonate, whereas they remained nine levels should be closely monitored during unchanged in the group treated with calcitriol treatment with calcitriol. Serum calcium and and sevelamer hydrochloride.23 phosphorus levels should be measured once It is hypothesized that calcitriol therapy weekly for 2 weeks after initiating therapy and should be initiated earlier in the course of then at least once a month for the first 6 months CRF and secondary hyperparathyroidism in of therapy. If hypercalcemia develops, calcitriol conjunction with a phosphorus-restricted supplementation should be discontinued. Only diet.6,27 Early intervention is important because after a normal serum calcium level is restored the PTH level can be high even with mild should supplementation be reinstituted at a azotemia.6 Dogs with CRF usually present lower dose. Serum PTH and creatinine levels with clinical signs of illness such as anorexia, should be measured 4 to 6 weeks after initiat- weight loss, vomiting, diarrhea, and dehydra- ing therapy to document calcitriol efficacy and tion and should be medically stabilized before to monitor the progression of renal disease. starting calcitriol therapy. Stabilization therapy If the PTH level is not suppressed by 4 to 6 usually includes intravenous fluids to correct weeks, the dose of calcitriol can be cautiously dehydration and reduce azotemia as well as increased or therapy can be discontinued.5 antiemetics and histamine-receptor antago- The owner and veterinarian should monitor nists (H2 blockers) to control vomiting. Use of the patient’s clinical signs, including changes antibiotics may be indicated by urine culture in appetite, thirst, urination, vomiting, diarrhea, results. Dietary phosphorus restriction to lower and energy level, for evidence of progression the serum phosphate level should be started of renal or parathyroid disease. once the patient has regained an appetite. Human formulations of calcitriol (Rocaltrol, Conclusion Roche) contain too much calcitriol for use in Although renal secondary hyperparathyroid- small animals. These 250- and 500-ng cap- ism is rare, it is an important disease to diag- sules cannot be readily divided, and custom nose and treat. Excess PTH may complicate reformulation by a pharmacist has been rec- the treatment of CRF and cause progression ommended to obtain appropriate dosages for of renal disease in dogs. Early diagnosis of individual pets.6,26 The current recommended renal disease and disturbances in calcium and dose for calcitriol in dogs is 2.5 ng/kg/day.27 phosphorus homeostasis are important to prevent the development of hyperparathyroidism. Vitamin D Analogs The diagnosis of secondary hyperparathyroid- Because of the risk of hypercalcemia with ism may be complicated if the serum calcium calcitriol supplementation, several vitamin level is elevated. Physical examination, histori- D analogs, including 22-oxacalcitriol (OCT), cal findings, and comprehensive and specific have been studied as alternatives to calcitriol diagnostics to rule out primary hyperparathy- in CRF patients. These analogs are thought to roid disease and other causes of hypercalce- suppress calcitriol and PTH levels but with a mia are important for making a diagnosis of lower occurrence of hypercalcemia.29 Clinical renal secondary hyperparathyroidism. trials in human dialysis patients receiving Dietary phosphorus restriction and the use intravenous OCT showed decreases in serum of phosphate binders can lower serum phos- PTH and increases in serum calcium to be phate and, subsequently, PTH levels, which has highly dose dependent.30 Experimental stud- been shown to slow the progression of renal ies in dogs have shown that both daily oral disease and extend the length of life of CRF and intermittent intravenous OCT administra- patients. It is also important to treat the clini- tion lower serum PTH levels without elevating cal signs of renal failure with appropriate fluid 31 iCa concentrations. However, despite some therapy, antiemetics, and H2 blockers and anti- promising experimental studies, further clini- biotics if indicated. Therapy with calcitriol may cal trials need to be done to prove the rela- decrease serum PTH levels further and may tive safety and efficacy of OCT compared with extend the quality and length of life in patients calcitriol. with renal secondary hyperparathyroidism.

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During treatment with calcitriol, it is impor- progression of renal disease and hyperparathy- tant to monitor serum calcium, phosphorus, roidism, such as appetite, thirst, urination, and creatinine, and PTH levels. There is a risk of vomiting, to assess treatment efficacy. Even hypercalcemia with calcitriol supplementa- with early diagnosis and treatment, CRF is a tion, and calcitriol should be used with cau- progressive and irreversible disease for which tion in combination with calcium-containing there is no cure, and the prognosis for animals phosphate binders. Owners and veterinarians with renal hyperparathyroidism is guarded to should monitor clinical signs associated with poor.

References 1. Greco D, Stabenfeldt GH. Endocrine glands and their function. Couto CG, eds. Essentials of Small Animal Internal Medicine. 3rd ed. In: Cunningham JG, ed. Textbook of Veterinary Physiology. 2nd ed. St. Louis: Mosby; 2003:681-690. Philadelphia: WB Saunders; 1997:404-439. 17. Ramsey IK, Tebb A, Harris E, et al. Hyperparathyroidism in dogs 2. Schenck PA, Chew DJ, Nagode LA, Rosol TJ. Disorders of cal- with hyperadrenocorticism. J Small Anim Pract 2005;46:531-536. cium: hypercalcemia and hypocalcemia. In: DiBartola SP, ed. Fluid, 18. Finco DR, Brown SA, Crowell WA, et al. Effects of dietary phos- Electrolyte, and Acid-Base Disorders in Small Animal Practice. 3rd phorus and protein in dogs with chronic renal failure. Am J Vet Res ed. St. Louis: WB Saunders; 2006:122-194. 1992;53:2264-2271. 3. Nelson RW, Feldman EC. Hypercalcemia and primary hyper- 19. Jacob F, Polzin D, Osborne CA, et al. Clinical evaluation of di- parathyroidism. In: Feldman EC, Nelson RW, eds. Canine and Feline etary modification for treatment of spontaneous chronic renal failure Endocrinology and Reproduction. 3rd ed. St. Louis: WB Saunders; in dogs. JAVMA 2002;220:1163-1170. 2004:659-715. 20. Emmett M. A comparison of clinically useful phosphorus bind- 4. Estepa JC, Aguilera-Tejero E, Lopez I, et al. Effect of phos- ers for patients with chronic kidney failure. Kidney Int 2004;66(sup- phate on parathyroid hormone secretion in vivo. J Bone Miner Res pl):25-32. 1999;14:1848-1854. 21. Cozzolino M, Staniforth ME, Liapis H, et al. Sevelamer hydrochlo- 5. Brown S, Finco DR. Reassessment of the use of calcitriol in ride attenuates kidney and cardiovascular calcifications in long-term chronic renal failure. In: Kirk RW, Bonagura JD, eds. Current Veteri- experimental uremia. Kidney Int 2003;64:1653-1661. nary Therapy XII, Small Animal Practice. Philadelphia: WB Saunders; 22. Duggal A, Hanus M, Zhorov E, et al. 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Kidney Int 2004;65:1914-1926. dogs with chronic renal failure. Am J Vet Res 2003;64:1181-1184. 25. Bleyer AJ, Burke SK, Dillon M, et al. A comparison of the calcium- 9. Polzin DJ, Ross S, Osborne CA. Calcitriol. In: Bonagura JD, Twedt free phosphate binder sevelamer hydrochloride with calcium acetate DC, eds. Current Veterinary Therapy XIV, Small Animal Practice. St. in treatment of hyperphosphatemia in hemodialysis patients. Am J Louis: WB Saunders; 2009:892-895. Kidney Dis 1999;33:694-701. 10. Kruger JM, Osborne CA, Nachreiner RF, et al. Hypercalcemia and 26. Chew DJ, Nagode LA. Calcitriol in the treatment of chronic renal renal failure. Vet Clin North Am Small Anim Pract 1996:26:1417- failure. In: Kirk BW, Bonagura JD, eds. Current Veterinary Therapy XI, 1445. Small Animal Practice. Philadelphia: WB Saunders; 1992:857-860. 11. Schenck PA, Chew DJ. Prediction of serum ionized calcium con- 27. Nagode LA, Chew DJ, Podell M. Benefits of calcitriol therapy and centration by use of serum total calcium concentration in dogs. Am J serum phosphorus control in dogs and cats with chronic renal fail- Vet Res 2005;26(8):1330-1336. ure. Both are essential to prevent or suppress toxic hyperparathyroid- 12. Kogika MM, Lustoza MD, Notomi MK, et al. Serum ionized cal- ism. Vet Clin North Am Small Anim Pract 1996;26:1293-1330. cium in dogs with chronic renal failure and metabolic acidosis. Vet 28. Polzin D, Ross S, Osborne C, et al. Clinical benefit of calcitriol Clin Pathol 2006;35:441-445. in canine chronic renal disease [ACVIM abstract 122]. Proc 23rd 13. Sarkiala EM, Dambach D, Harvey CE. Jaw lesions resulting from ACVIM 2005: 874. renal hyperparathyroidism in a young dog—a case report. J Vet Dent 29. Monier-Faugere MC, Geng Z, Friedler RM. 22-Oxacalcitriol sup- 1994;11:121-124. presses secondary hyperparathyroidism without inducing low bone 14. Forest LJ. The cranial and nasal cavities—canine and feline. 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1. Before starting treatment with calcitriol, a. decreased renal calcitriol synthesis a. Primary hyperparathyroidism which of the following should be done? b. increased serum phosphate level b. Hypothyroidism a. correct dehydration with intravenous c. high serum protein levels c. CRF fluids d. a and b d. Hyperadrenocorticism b. control vomiting and nausea with anti-

emetics and H2 blockers 5. An elevated serum PTH level can cause 8. Which therapy is used to treat renal c. start a phosphorus-restricted diet a. pathologic fractures. secondary hyperparathyroidism? d. all of the above b. cardiac arrhythmias. a. dietary phosphorus restriction c. symmetric swelling of the maxilla and b. oral calcium binders 2. ______is not a hormone involved in mandible. c. calcidiol supplementation the control of calcium homeostasis. d. a and c d. parathyroid gland ablation a. Calcitriol b. Cortisol 6. Which statement regarding the PTH 9. ______is a potential adverse effect of c. PTH radioimmunoassay test is correct? calcitriol therapy. d. Calcitonin a. Dogs with hypercalcemia unrelated a. Hepatic failure to parathyroid disease always have b. Gastric ulceration 3. What diagnostic test(s) can be done to decreased PTH levels. c. Hypercalcemia differentiate CRF from other causes of b. The PTH level should be evaluated relative d. Muscle weakness hypercalcemia? to total calcium and iCa concentrations. a. serum lactate measurement c. Only dogs with primary hyperparathy- 10. Serum ______should be monitored b. lymph node aspiration roidism have elevated PTH levels. during treatment with calcitriol. c. serum calcitriol measurement d. PTH concentrations can be measured a. calcium d. b and c on an in-house blood analyzer. b. phosphorus c. creatinine 4. Which mechanism(s) may cause hyper- 7. ______generally causes an increase d. all of the above parathyroidism secondary to CRF? in the serum calcitriol level.

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