USE OF CALCITRIOL (1,25 (OH)2 VITAMIN D) IN CHRONIC RENAL DISEASE:
AN EFFECTIVE TREATMENT FOR EXCESS PARATHYROID HORMONE (PTH)

Larry A. Nagode, Dennis J. Chew, Marcia A. Carothers & Carole L. Steinmeyer

I. Renal secondary hyperparathyroidism affects at least 5 million dogs and cats today in U.S.

• A. Why important? - High PTH is toxic decreasing quality and length of life:

1.     Bone effects - renal osteodystrophy
2.     Central and peripheral nervous system toxicity of excess PTH
3.     Cardiac and skeletal muscular toxicity of excess PTH
4.     Red and white blood cell toxicity of excess PTH
5.     Damage to energy metabolism and appetite caused by excess PTH
6.     Damage to kidney by excess PTH -> progression of renal disease

•   B. Causes of hyperparathyroidism in renal failure:

1. Each of the 3 previously accepted "classic" causes of  renal secondary hyperparathyroidism is now explained via a common mechanism of the deficit of calcitriol occurring in these patients.

II. Causes of calcitriol deficits in renal failure:

• A. Loss of renal tubular sites of calcitriol formation -nephritis or nephrosis.

• B. Hyperphosphatemia due to decreased Pi clearance - inhibits calcitriol synthesis.

III. Mechanisms of the benefit from low doses of calcitriol in dogs & cats with renal failure:

• A. Calcitriol blocks PTH synthesis and secretion at the parathyroid gland.

1. It does not require or cause elevation of blood calcium to work so there is little concern with hypercalcemic toxicity sometimes seen with vitamin D or dihydrotachysterol which have very long half lives in the body compared to the 4-6 hr half life of calcitriol.

• B. Calcitriol blocks cellular hyperplasia in parathyroid glands of uremic animals and causes regression of pre-existing hyperplasia.  Both result in lowered PTH.

• C. Calcitriol decreases the number of receptors for PTH in target tissues thus decreasing the amount of damage high levels of PTH can do.

• D. Because calcitriol is an early evolved hormone with many direct beneficial effects in the body its replacement in uremic animals is important in ways independent of its role to lower blood levels of PTH.

IV. Corrective therapy for hyperparathyroidism:

• A. Normalize serum phosphorus - successful if patients retain enough tubules to synthesize adequate calcitriol without the stimulation of high serum PTH.

1. Most effective for patients with mild uremia and PTH  elevations.
2. Necessary to partially lower PTH in all uremic patients with elevated serum phosphorus.

• B. Low daily oral doses of calcitriol directly correct the primary cause of excess blood PTH, i.e., calcitriol deficit.  This is done after serum Pi  lowered to < 6 mg/dl.

V. When to initiate calcitriol therapy in uremic dogs and cats:

• A. Do not wait for hypocalcemia or overt bone disease.

1. Deficits of total blood calcium are rare in uremic patients.
2. Other damage of high PTH occurs much before obvious bone disease.

• B. After lowering serum Pi level to no more than 6 mg/dl (3-5 mg/dl optimally).

1. Ca X Pi product should not exceed 70 to avoid soft tissue mineralization.
2. Fear of calcitriol stimulating gut calcium absorption -> hypercalcemia.
• a. a. Minimal problem with low daily doses (2.5-3.5 ng/kg) recommended. When [problem] occurs intermittent (every 3.5 day) dosing can be used at 3.5 times the daily dose to decrease the intestinal effects of calcitriol on calcium absorption. [See fasting and dosing on this web site.]
3. Serum Pi management is important irrespective of other treatments.
• a. Calcitriol is ineffective at parathyroid gland if serum Pi is high enough (> 8 mg/dl) to  significantly lower ionized calcium (Ca++) in blood as a normal Ca++ is synergistic with calcitriol there.

• C. Most symptomatic uremic dogs and cats are hyperparathyroid -84% of uremic cats were hyperparathyroid in a 1999 study.

• D. A preventive use of a low (2.5-3.5 ng/kg) dose of calcitriol to supplement dogs and cats in early stages of chronic renal  disease appears safe, effective and advisable.

Calcitriol is available by prescription for dogs and cats of varying sizes from Triad Compounding Pharmacy in California, Toll-free: 1-800-851-7900, Local: 1-562-468-4311, FAX: 1-562-468-4314.  (see editors note below)

[Editor's note:  Compounded calcitriol for animal use is available from many other compounding pharmacies in the US.  Triad is the only one that Dr. Nagode personally recommends because it is the only one that he has personal knowledge of its compounding procedures.  If you are thinking about using another provider, Dr. Nagode suggests that your vet or your should " ... check in with the proposed providing pharmacy" simply inquiring "what is done to protect vs. oxidative injury?".  If the question is met with a puzzled response or the statement that 'we just dilute a stock solution from wholesaler', then a request that they look into the matter should be made--and if they lack interest in so doing, an alternative provider should be sought." "Calcitriol when compounded for veterinary use needs to have stabilizing agents included to protect its 3 alcoholic groups from oxidation by the polyunsaturated oils used to dilute the calcitriol. Veterinarians are encouraged to use one of the more experienced compounding pharmacies to ensure stable appropriate dosages."