Hyperparathyroidism, hyperphosphatemia and low or normal calcium

Dialysis Prescription

Significant prolongation of dialysis times (nocturnal dialysis) may bring about reduction in phosphate and help control calcium levels.  Daily intermittent dialysis up to 5 hours may have little effect. There is no advantage to changing the dialysate bath in this situation.

Phosphate and Calcium Management

Therapeutic avenues include:

• Increasing the dose of calcium containing phosphate binder.
• Combining calcium and non-calcium containing phosphate binders

Dietary phosphate intake and adherence to dose and timing of binder ingestion should be reviewed. If the calcium level is below or at the lower level of the normal range, an increase in the dose of calcium binder is indicated since the low calcium may be driving the hyperparathyrodism.

If the patient has had previous hypercalcemia, or if the calcium is at the upper level of the normal range, the addition, or increase in the dose, of a non-calcium containing binder is reasonable.  A combination of non-calcium and calcium containing binders can be used effectively to minimize hypercalcemia and to reduce the costs of the non-calcium binders.

PTH Management

An increase in calcium based binder may lower the PTH. Active vitamin D sterols would not be indicated until the phosphate was under better control.  If they are being used, it may be necessary to lower the dose to reduce phosphate absorption.

If the PTH level is very high (> 100 pmol/L) or has been consistently above 75 pmol/L, consideration should be given to the initiation of a calcimimetic.   This will have an effect to lower the PTH, and is also likely to bring about some reduction in phosphate level.  However, a lowering of the calcium level may also be seen: this would allow an increase in the calcium-containing phosphate binder dose.  If a calcimimetic is being used, then an effort should be made to raise the calcium well into the normal range to allow the calcimimetic to have its best effect.  If the calcium is already in the high normal range, an increase in the dose of calcimimetic should be considered.

More aggressive measures to control the hyperparathyroidism such as parathyroidectomy if the PTH level is very high, or has been chronically unresponsive to medical management should be considered.

Other Options of Controversies in Management

Total Dose of Calcium

It remains unclear what total daily dose of calcium is safe in dialysis patients.  In a review of phosphate binders, Hutchinson has suggested that with standard dialysis in a patient with a calcium intake of 1000 mg, the addition of 4 x 1250mg calcium carbonate tablets will result in a weekly accrual of as much as 3500 mg elemental calcium.  If it were not for the cost factor, most nephrologists would prefer not to have this degree of calcium accumulation.

The K/DOQI guidelines are restrictive on the total amount of calcium which should be used:

GUIDELINE 5. USE OF PHOSPHATE BINDERS IN CKD

5.5 The total dose of elemental calcium provided by the calcium-based phosphate binders should not exceed 1,500 mg/day (OPINION), and the total intake of elemental calcium (including dietary calcium) should not exceed 2,000 mg/day. (OPINION)

Favour non-calcium containing binders when vascular calcification is present:

5.7 Noncalcium-containing phosphate binders are preferred in dialysis patients with severe vascular and/or other soft tissue calcifications. (OPINION)

The following position was adopted by the KDIGO group:

Chapter 4.1: Treatment of CKD–MBD targeted at lowering high serum phosphorus and maintaining serum calcium

4.1.5 In patients with CKD stages 3–5D and hyperphosphatemia, we recommend restricting the dose of calcium-based phosphate binders and/or the dose of calcitriol or vitamin D analog in the presence of persistent or recurrent hypercalcemia (1B).

In patients with CKD stages 3–5D and hyperphosphatemia, we suggest restricting the dose of calcium based phosphate binders in the presence of arterial calcification (2C) and/or adynamic bone disease (2C) and/or if serum PTH levels are persistently low (2C).

Use of Calcimimetics

Calcimimetic use has been associated with better control of parameters of mineral metabolism under “real world” conditions.

The KDIGO group offers these considerations on their use:

Chapter 4.2: Treatment of abnormal PTH levels in CKD–MBD

4.2.4 In patients with CKD stage 5D and elevated or rising PTH, we suggest calcitriol, or vitamin D analogs, or calcimimetics, or a combination of calcimimetics and calcitriol or vitamin D analogs be used to lower PTH (2B).

- It is reasonable that the initial drug selection for the treatment of elevated PTH be based on serum calcium and phosphorus levels and other aspects of  CKD–MBD (not graded).

- It is reasonable that calcium or non-calcium-based phosphate binder dosage be adjusted so that treatments to control PTH do not compromise levels of phosphorus and calcium (not graded).

- We suggest that, in patients with hyperphosphatemia, calcitriol or another vitamin D sterol be reduced or stopped (2D).

- We suggest that, if the intact PTH levels fall below two times the upper limit of normal for the assay, calcitriol, vitamin D analogs, and/or calcimimetics be reduced or stopped (2C).

Suggested References

1. Oral phosphate binders. Manchester Institute of Nephrology and Transplantation, The Royal Infirmary, Manchester, UK. [email protected]
   Hyperphosphatemia is an inevitable consequence of end-stage chronic kidney disease and is present in the majority of dialysis patients. Hyperphosphatemia is observationally and statistically associated with increased cardiovascular mortality among dialysis patients. Dietary restriction of phosphate and current dialysis modalities are not sufficiently effective to maintain serum phosphate levels within the recommended range, so the majority of dialysis patients require oral phosphate binders. However, the benefits of achieving the recommended range have yet to be shown prospectively. Unfortunately, conventional phosphate binders are not reliably effective and are associated with a range of limitations and side effects. Aluminum-containing agents are highly efficient but no longer widely used because of proven toxicity. Calcium-based salts are inexpensive, effective, and most widely used, but there is now concern about their association with hypercalcemia and vascular calcification. Sevelamer hydrochloride is associated with fewer adverse effects, but a large pill burden and high cost are limiting factors to its wider use. Lanthanum carbonate is another non-aluminum, calcium-free phosphate binder. Preclinical and clinical studies have shown a good safety profile, and it appears to be well tolerated and effective in reducing phosphate levels in dialysis patients; however, it is similarly expensive. Data on its safety profile over 6 years of treatment are now published. Achievement of opinion-based guidelines appears to have become an end in itself. Dialysis patient outcomes are worse than outcomes for many types of cancer, yet prospective, outcome-based randomized controlled trials are not being undertaken for reasons that are difficult to explain.
2. Phosphate binders: hold the calcium? Department of Medicine, University of Rochester School of Medicine, Nephrology Division, Strong Memorial Hospital, 601 Elmwood Avenue, Box 675, Rochester, NY 14642, USA. [email protected] Link: http://www.ncbi.nlm.nih.gov/pubmed/17699274?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=11
3. The OPTIMA study: assessing a new cinacalcet (Sensipar/Mimpara) treatment algorithm for secondary hyperparathyroidism. Nephrology Division, CROFF Policlinico di Milano, Via Della Commenda, 20122 Milano, Italy. [email protected]
   BACKGROUND AND OBJECTIVES: Cinacalcet, a novel calcimimetic, targets the calcium-sensing receptor to lower parathyroid hormone (PTH), calcium, and phosphorus levels in dialysis patients with secondary hyperparathyroidism (SHPT). This study compared the efficacy of a cinacalcet-based regimen with unrestricted conventional care (vitamin D and phosphate binders) for achieving the stringent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) targets for dialysis patients. Study design: In this multicenter, open-label study, hemodialysis patients with poorly controlled SHPT were randomized to receive conventional care (n = 184) or a cinacalcet-based regimen (n = 368). Doses of cinacalcet, vitamin D sterols, and phosphate binders were adjusted during a 16-wk dose-optimization phase with the use of algorithms that allowed cinacalcet to be used with adjusted doses of vitamin D. The primary end point was the proportion of patients with mean intact PTH < or =300 pg/ml during a 7-wk efficacy assessment phase. RESULTS: A higher proportion of patients receiving the cinacalcet-based regimen versus conventional care achieved the targets for PTH (71% versus 22%, respectively; P < 0.001), Ca x P (77% versus 58%, respectively; P < 0.001), calcium (76% versus 33%, respectively; P < 0.001), phosphorus (63% versus 50%, respectively; P = 0.002), and PTH and Ca x P (59% versus 16%, respectively, P < 0.001), and allowed a 22% reduction in vitamin D dosage in patients receiving vitamin D at baseline. Achievement of targets was greatest in patients with less severe disease (intact PTH range, 300 to 500 pg/ml) and the cinacalcet dose required was lower in these patients (median = 30 mg/d). CONCLUSIONS: Compared with conventional therapy, a cinacalcet-based treatment algorithm increased achievement of KDOQI treatment targets in dialysis patients in whom conventional therapy was no longer effective in controlling this disease. Link: http://www.ncbi.nlm.nih.gov/pubmed/18178780?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2