section name header

Basics ⬇

Basics

Overview

  • Clinical syndrome characterized by a high concentration of biologically active PTH secondary to chronic kidney disease; results from impaired renal excretion of phosphorus leading to elevated levels of fibroblastic growth factor-23 (FGF-23) and associated suppression of renal calcitriol synthesis; low concentrations of ionized calcium and hyperphosphatemia also contribute.
  • Hyperphosphatemia secondary to declining renal function is associated with an increase in phosphatonin FGF-23 which enhances renal phosphaturia and reduces the activity of 1--hydroxylase in the kidney, which in turn reduces production of calcitriol (1,25-dihydroxycholecalciferol). In more advanced CKD, reduced renal tubular mass also contributes to reduced calcitriol synthesis. Normal calcitriol concentrations exert a negative effect on PTH synthesis within the parathyroid gland nucleus. Low calcitriol and serum ionized calcium concentrations and hyperphosphatemia result in increased PTH production and parathyroid gland hyperplasia.
  • PTH may act as a uremic toxin and may promote nephrocalcinosis and progression of chronic renal failure.

Signalment

Dog and cat. See Renal Failure, Chronic, for age and breed predilections.

Signs

  • Those associated with underlying chronic kidney disease are the usual reason for examination.
  • Severe renal osteodystrophy or “rubber jaw” occurs in some patients, most commonly young dogs with severe renal secondary hyperparathyroidism.
  • Pain around the head or bone pain-sometimes very marked.

Causes & Risk Factors

  • Any disease that causes chronic kidney disease
  • Excess consumption of dietary phosphorus

Diagnosis ⬆ ⬇

Diagnosis

Differential Diagnosis

  • Hypercalcemic nephropathy-renal disease (or failure) caused by ionized hypercalcemia; can be difficult to differentiate from long-standing renal secondary hyperparathyroidism in which hyperplasia of the parathyroid glands limits their ability to stop releasing PTH in the face of high concentrations of ionized calcium (tertiary hyperparathyroidism).
  • The total serum calcium concentration is usually higher in patients with hypercalcemic nephropathy than in those with renal secondary hyperparathyroidism; the ionized serum calcium concentration is usually low or normal with renal secondary hyperparathyroidism, but high with hypercalcemic nephropathy.
  • Serum PTH concentration is low and PTHrP high in animals with hypercalcemia of malignancy; may detect underlying causes of hypercalcemia such as lymphoma or apocrine gland adenocarcinoma of the anal sac.
  • Primary hyperparathyroidism-initially characterized by hypercalcemia (ionized and total), normal or low serum phosphorus concentration, and high PTH concentration; renal function is initially normal but may become compromised later in the course of disease.

CBC/Biochemistry/Urinalysis

  • Azotemia.
  • Hyperphosphatemia.
  • Urine specific gravity <1.030 in dogs and <1.035 in cats.
  • Total serum calcium concentration may be low, normal, or slightly increased; see Renal Failure, Chronic.

Other Laboratory Tests

  • Definitive diagnosis and therapeutic monitoring of renal secondary hyperparathyroidism require measurement of serum PTH concentration; an immunoassay for PTH directed against the amino-terminal or intact PTH molecule and validated for dogs or cats is necessary for reproducible and meaningful results.
  • A low-to-normal ionized serum calcium concentration is useful to differentiate renal secondary hyperparathyroidism from other causes of hypercalcemia.

Imaging

Radiographs may reveal low bone density, loss of the lamina dura around the teeth, and soft-tissue mineralization of the gastric mucosa or other tissues.

Treatment ⬆ ⬇

Treatment

Medications ⬆ ⬇

Medications

Drug(s)

Intestinal Phosphate Binders

  • Prescribe if dietary management does not return phosphorus concentration to recommended levels: serum phosphate <4.5 mg/dL for dogs and cats in IRIS CKD stage 2; <5.0 mg/dL in IRIS CKD stage 3; and <6.0 mg/dL in IRIS CKD stage 4.
  • Aluminum hydroxide (30–90 mg/kg/day PO with meals), calcium carbonate (90–150 mg/kg/day PO with meals), calcium acetate (60–90 mg/kg/day PO with meals), or lanthanum carbonate (same dosing as aluminum hydroxide). Dose to effect to achieve stated serum phosphorus concentration target, but do not exceed recommended dosage.
  • Hypercalcemia may develop when a calcium-containing phosphate binder is combined with calcitriol; calcium-containing phosphate binders should be avoided with calcitriol therapy. Chemically different phosphate binders can be used in combination to reduce the dosage of each and minimize the risk of hypercalcemia or aluminum toxicity.

Calcitriol

  • Low-dose calcitriol (2.0–3.5 ng/kg PO q24h)-may use after initiation of dietary phosphorus restriction and oral phosphate binders; note that this dose is in ng/kg rather than mg/kg; a pharmacy that specializes in reformulation of calcitriol into low doses is needed to provide this prescription. Calcitriol should be administered on an empty stomach and before bedtime (i.e., no food for 6–8 hours after administration).
  • Maintain serum phosphorus concentration within the target range before and during calcitriol therapy: serum phosphorus <4.5 mg/dL in CKD stage 2; <5.0 mg/dL in CKD stage 3; and <6.0 mg/dL in CKD stage 4.

Contraindications/Possible Interactions

  • Calcitriol administration may result in hypercalcemia, especially if combined with a calcium-containing intestinal phosphate binder. Increased total calcium concentration sometimes develops in patients with long-standing chronic kidney disease but is not related to calcitriol treatment. In these instances, ionized calcium concentration is normal or low, and hypercalcemia does not resolve when calcitriol treatment is discontinued.
  • Do not use calcium-containing intestinal phosphate binders in patients with a calcium × phosphorus product >70. Use aluminum-containing or lanthanum-containing intestinal phosphate binders initially to correct hyperphosphatemia. Calcium-containing intestinal phosphate binders can be reconsidered once the serum phosphorus concentration is within the target range.

Follow-Up ⬆ ⬇

Follow-Up

Patient Monitoring

  • Initially and in unstable patients, serum concentrations of calcium, phosphorus, creatinine, and urea nitrogen-monitor weekly to monthly depending on therapy and the severity of chronic kidney disease.
  • Patients receiving calcitriol should be monitored for hypercalcemia and/or hyperphosphatemia weekly for 4 weeks, then monthly if the patient is stable, and then every 3–4 months.
  • Serial evaluations of PTH concentration-most dogs and cats treated with low doses of calcitriol achieve near-normal levels of PTH within 3 months; it may be necessary to increase the dose in those with severe parathyroid gland hyperplasia.
  • If hypercalcemia develops, discontinue use of calcitriol. Measurement of ionized calcium is recommended since some animals with chronic kidney disease develop non-ionized hypercalcemia that is unrelated to calcitriol treatment. If hypercalcemia is due to calcitriol treatment (high-ionized calcium), it should abate within 5 days. Intermittent-dose calcitriol treatment at twice the dose every other day may alleviate a mild degree of hypercalcemia. Patients with more severe hypercalcemia may benefit from 3.5 times the normal dose given every 3.5 days. These effects on reduction in hypercalcemia are due to decreased programming of intestinal epithelial cells for calcium absorption.

Prevention/Avoidance

Dietary phosphorus restriction in patients with chronic kidney disease may delay the onset of renal secondary hyperparathyroidism.

Possible Complications

Renal osteodystrophy and pathologic fractures (rare)

Expected Course and Prognosis

  • Progression of the underlying chronic kidney disease may be slowed by minimizing phosphorus retention and renal secondary hyperparathyroidism.
  • Long-term prognosis is guarded to poor for patients with chronic kidney disease and renal secondary hyperparathyroidism.

Miscellaneous ⬆

Miscellaneous

Age-Related Factors

Young animals can develop severe renal osteodystrophy and may benefit from treatment with calcitriol.

Abbreviations

  • CKD = chronic kidney disease
  • PTH = parathyroid hormone

Author David J. Polzin

Consulting Editor Carl A. Osborne

Suggested Reading

Polzin D. Chronic kidney disease. In: Ettinger SJ, Feldman EC, eds., Textbook of Veterinary Internal Medicine, 7th ed. St. Louis, MO: Elsevier, 2009, pp. 2036–2067.

Polzin DJ, Ross SJ, Osborne CA. Calcitriol therapy in chronic kidney disease. In: Bonagura J, ed., Current Veterinary Therapy XIV. Philadelphia: Saunders, 2008, pp. 892–895.