Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease: An Overview

George R. Bailie, PharmD, PhD, FCCP; Shaul G. Massry, MD

Disclosures

Pharmacotherapy. 2005;25(12):1687-1707. 

In This Article

Guideline 8: Vitamin D Therapy in Patients with Chronic Kidney Disease

Guideline 8A. Active Vitamin D Therapy in Stages 3 and 4 (Figure 3)

Figure 3.

Treatment of patients with stages 3 and 4 CKD with active vitamin D sterols. PTH = parathyroid hormone. Guidelines 1, 4, and 5 are specific K/DOQI guidelines. (Adapted with permission from reference 3, algorithm 2.)

Guideline Statements

8A.1 - In patients with stages 3 and 4 CKD, therapy with an active oral vitamin D sterol (calcitriol, alfacalcidol, or doxercalciferol) is indicated when serum concentrations of 25(OH)D are above 30 ng/ml (75 nmol/L), and plasma concentrations of iPTH are above the target range for the CKD stage (E). Initial dosages are provided in Table 7 .

 

8A.1a - Treatment with an active vitamin D sterol should be undertaken only in patients with serum concentrations of corrected total calcium below 9.5 mg/dl (2.37 mmol/L) and serum phosphorus concentrations below 4.6 mg/dl (1.49 mmol/L) (O).

 

 

8A.1b - Vitamin D sterols should not be prescribed for patients with rapidly worsening kidney function or those who are noncompliant with drug therapies or follow-up (O).

 

8A.2 - During therapy with vitamin D sterols, serum calcium and phosphorus concentrations should be monitored at least every month after start of therapy for the first 3 months, then every 3 months thereafter. Plasma PTH concentrations should be monitored at least every 3 months for 6 months, and every 3 months thereafter (O).

8A.3 - Dosage adjustments for patients receiving active vitamin D sterol therapy should be made as follows:

 

8A.3a - If plasma iPTH concentrations decrease below the target range for the CKD stage, hold active vitamin D sterol therapy until plasma concentrations of iPTH increase to above the target range, then resume treatment with the dosage of active vitamin D sterol reduced by half. If the lowest daily dose of the active vitamin D sterol is being used, reduce to alternate-day dosing (O).

 

 

8A.3b - If serum concentrations of corrected total calcium exceed 9.5 mg/dl (2.37 mmol/L), hold active vitamin D sterol therapy until serum calcium concentration returns to less than 9.5 mg/dl (2.37 mmol/L), then resume treatment at half the previous dose. If the lowest daily dose of the active vitamin D sterol is being used, reduce to alternate-day dosing (O).

 

 

8A.3c - If serum concentrations of phosphorus increase to greater than 4.6 mg/dl (1.49 mmol/L), hold active vitamin D therapy, begin or increase dosage of phosphorus binder until the concentrations of serum phosphorus decrease to 4.6 mg/dl (1.49 mmol/L) or less; then resume the prior dose of active vitamin D sterol (O).

 

Note that these guidelines are largely opinion based. Active vitamin D sterols are useful in the treatment of secondary hyperparathyroidism and high-turnover bone disease in early stages of CKD before these derangements advance and their treatment becomes more difficult. Oral administration of small doses of the vitamin D sterols reduce plasma iPTH concentrations, improve bone histology, and lead to increased bone mineral density. With the use of low doses, these effects occur with no evidence of worsening of kidney function; however, careful monitoring of serum calcium and phosphorus concentrations and plasma iPTH concentrations is essential.

Guideline 8B. Vitamin D Therapy in Stage 5 (Figures 4-6)

Figure 4.

Managing vitamin D sterols based on serum calcium concentrations. PTH = parathyroid hormone. (Adapted with permission from reference 3, algorithm 3.)

Figure 5.

Managing vitamin D sterols based on serum phosphorus concentrations. PTH = parathyroid hormone. (Adapted with permission from reference 3, algorithm 4.)

Figure 6.

Managing vitamin D sterols based on intact parathyroid hormone (iPTH) concentrations. When intact plasma PTH concentration is 300-500 pg/ml (33.0-55.0 pmol/L) and changes on two successive determinations are small (< 25%), there is no need to modify vitamin D dosage as long as serum phosphorus and calcium concentrations are within the desired limits (Figures 4 and 5). When intact plasma PTH concentration is persistently greater than 500 pg/ml (55.0 pmol/L) and serum phosphorus concentration is 5.5-6.5 mg/dl (1.78-1.94 mmol/L) and/or serum calcium concentration is 10.2-10.5 mg/dl (2.54-2.62 mmol/L), a trial with a "less calcemic" analog may be warranted for 3-5 months. If the patient fails to respond, parathyroidectomy may be required. (Adapted with permission from reference 3, algorithm 5.)

Guideline Statements

8B.1 - Patients treated with hemodialysis or peritoneal dialysis, with plasma concentrations of iPTH greater than 300 pg/ml (33.0 pmol/L [equivalent to biPTH > 150 pg/ml]) should receive an active vitamin D sterol (such as calcitriol, alfacalcidol, paricalcitol, or doxercalciferol; Table 8 ) to reduce the plasma concentrations of iPTH to a target range of 150-300 pg/ml (16.5-33.0 pmol/L [biPTH 75-150 pg/ml]) (E).

 

8B.1a - Intermittent, intravenous administration (known as pulse dosing) of calcitriol is more effective than daily oral calcitriol in lowering plasma PTH concentrations (E).

 

 

8B.1b - In patients with corrected serum calcium and/or phosphorus concentrations above the target range, a trial of alternative vitamin D analogs, such as paricalcitol or doxercalciferol, may be warranted (O).

 

8B.2 - When therapy with vitamin D sterols is begun or the dosage is increased, serum calcium and phosphorus concentrations should be monitored at least every 2 weeks for 1 month and then monthly thereafter. The plasma PTH should be measured monthly for at least 3 months and then every 3 months once target concentrations of PTH are achieved (O).

8B.3 - For patients treated with peritoneal dialysis, oral doses of calcitriol (0.5-1.0 µg) or doxercalciferol (2.5-5.0 µg) can be given 2 or 3 times/week. Alternatively, a lower dose of calcitriol (0.25 µg) can be administered daily (O).

8B.4 - When patients undergoing either hemodialysis or peritoneal dialysis are treated with active vitamin D sterols, management should integrate the changes in serum calcium, serum phosphorus, and plasma PTH concentrations (O). Each of these three variables is considered separately with suggested interventions based on the various values obtained in Figures 4-6.

In patients with end-stage renal disease, treatment of secondary hyperparathyroidism with calcitriol, paricalcitol, doxercalciferol, or alfacalcidol can reduce the elevated iPTH concentrations, resulting in improved features of hyperparathyroid bone disease.

Adverse Effects from Vitamin D Analogs

Administration of vitamin D analogs can stimulate vitamin D receptors in many tissues. A major adverse effect of vitamin D treatment is increased intestinal absorption of calcium and phosphorus, due to stimulation of vitamin D receptors in the gastrointestinal system. As a result, hypercalcemia may appear, hyperphosphatemia may be aggravated, and both may lead to the problems associated with elevations in the calcium-phosphorus product. Acute hypercalcemia is also a potential problem, especially when corrected serum calcium concentrations exceed 10.5 mg/dl. The newer vitamin D2 analogs, paricalcitol and doxercalciferol, may be less likely to cause hypercalcemia.

Also, treatment with vitamin D sterols can markedly lower plasma concentrations of iPTH and lead to adynamic bone disease. Occurrence of adynamic bone disease is nearly universal when iPTH concentrations are below 65 pg/ml (7.15 pmol/L). Mild hyperparathyroid bone disease may be preferable to adynamic bone disease because of the loss of the capacity of bone buffering for the added extracellular calcium; this may account for the increased risk of hypercalcemia in patients with adynamic bone disease. The long-term risks of chronic calcium loading under these circumstances was previously discussed.

Thus, serum calcium and phosphorus concentrations and plasma PTH concentrations must be monitored during vitamin D therapy, and vitamin D therapy adjusted accordingly (Figures 4-6). The interplay between calcium, phosphorus, and PTH concentrations is complex and has led to the generation of three separate algorithms. These can be used to assist the decision-making process regarding vitamin D dosage adjustments based on changes in calcium (Figure 4), phosphorus (Figure 5), or PTH (Figure 6) concentrations. In reality, in patients treated with vitamin D therapy, all these variables change simultaneously when the vitamin D dosage is altered. Fortunately, most patients in the later stages of CKD will be treated by nephrologists who will be experienced in the management of bone diseases. Nevertheless, some patients, especially those not followed by a nephrologist or those treated with peritoneal dialysis or in stages of kidney disease before the need for dialysis therapy, may be seen with reduced frequency. Under these circumstances, additional oversight by other health care professionals might be appropriate.

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