Hyperparathyroidism, desired phosphate and hypercalcemia

Dialysis Prescription

A reduction in the dialysate calcium concentration from 1.25 to 1.0 mmol/L might help with the hypercalcemia, but would introduce a stimulus which might further increase the PTH level.

Phosphate and Calcium Management

Therapeutic avenues include:

• Adding a non-calcium containing binder while lowering the dose of any calcium containing binder
• Switching from a calcium to an non-calcium binder

Phosphate is normal in this patient.  Ongoing counseling about phosphate in the diet and the timing of binders with respect to meals is required. The dose of any calcium containing phosphate binder in this patient needs to be reassessed given the hypercalcemia.  The dose of calcium binder would need to be reduced, which may aggravate the hyperparathyroidism and result in loss of control of the phosphate.

It is reasonable to add or increase the dose of a non-calcium containing binder in this patient. A combination of non-calcium and calcium containing binder (at a lower dose) can be used effectively to minimize hypercalcemia and to reduce the costs of the non-calcium binders.

PTH Management

Trial of a less calcemic vitamin D analogue such as doxercalciferol or paracalcitol. Initiation or increased dose of a calcimimetic will have an effect to lower the PTH, and is also likely to bring about some reduction in calcium and the phosphate level.  A lowering of the calcium level may also permit the current dose of calcium-containing binder to be maintained. 

Parathyrodectomy should be considered if the patient has persistent hypercalcemia and if the PTH has been chronically elevated, or if alkaline phosphatase level was elevated.

Other Controversies in Management

There are very few data examining the role of combining phosphate binders to limit exposure to the potential toxicities of aluminum, calcium, and magnesium.

The K/DOQI group has the following opinion:

GUIDELINE 5. USE OF PHOSPHATE BINDERS IN CKD
5.4 In dialysis patients who remain hyperphosphatemic (serum phosphorus >5.5 mg/dL [1.78 mmol/L]) despite the use of either of calcium-based phosphate binders or other noncalcium-, nonaluminum-, nonmagnesium-containing phosphate-binding agents, a combination of both should be used. (OPINION)

The KDIGO group makes no mention of combinations of phosphate binders:

Chapter 4.1: Treatment of CKD–MBD targeted at lowering high serum phosphorus and maintaining serum calcium
4.1.4 In patients with CKD stages 3–5 (2D) and 5D (2B), we suggest using phosphate-binding agents in the treatment of hyperphosphatemia. It is reasonable
that the choice of phosphate binder takes into account CKD stage, presence of other components of CKD–MBD, concomitant therapies, and side-effect profile (not graded).


Nonetheless, it seems very reasonable to combine calcium and non-calcium binders in an effort to minimize the cost of using the more expensive calcium binders alone.

Measuring Alkaline Phosphatase
Older data suggest that the measurement of total alkaline phosphatase activity may be useful in improving the accuracy of a diagnosis of significant hyperparathyroidism.  The measurement of bone specific alkaline phosphatase may be even more useful, but is less readily available and more expensive.

Urena P, et al: Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients. J Bone Miner Res 10:932-939, 1995

More recently, there has been interest in the level of alkaline phosphatase as a predictor of mortality.

Regidor DL, et al.  Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients. J Am Soc Nephrol. 2008;19:2193.

While the K/DOQI group did not recommend regular monitoring of the alkaline phophastase, the KDIGO group adopted this position:

Chapter 3.1: Diagnosis of CKD–MBD: biochemical Abnormalities
3.1.1. We recommend monitoring serum levels of calcium, phosphorus, PTH, and alkaline phosphatase activity beginning in CKD stage 3 (1C). In children, we suggest
such monitoring beginning in CKD stage 2 (2D).
3.1.2. In patients with CKD stages 3–5D, it is reasonable to base the frequency of monitoring serum calcium, phosphorus, and PTH on the presence and magnitude of abnormalities, and the rate of progression of CKD (not graded).

Reasonable monitoring intervals would be:
In CKD stages 4–5D: for alkaline phosphatase activity, every 12 months, or more frequently in the presence of elevated PTH

It is not clear how much the regular monitoring of bone specific alkaline phosphatase adds to the clinical context

References

1. Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients.

Harold Simmons Center for Kidney Disease Research and Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90509-2910, USA.

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.
Link: http://www.ncbi.nlm.nih.gov/pubmed/18667733?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1

2. Serum pyridinoline as a specific marker of collagen breakdown and bone metabolism in hemodialysis patients.

Departement de Nephrologie, INSERM Unité 90, Hôpital Necker-Enfants Malades, Paris, France.
Type I collagen represents more than 90% of bone matrix. Quantitative analysis of collagen cross-link molecules such as pyridinoline (PYD) provides valuable information on bone resorption rate. We have studied 37 hemodialysis patients who underwent a systematic transiliac bone biopsy for histomorphometry study. Eighteen of them had tetracycline double labeling, allowing to determine dynamic, in addition to static bone parameters. Measurement of serum-free PYD was performed using a new competitive enzyme immunoassay. Serum PYD values were compared with those of three other serum markers of bone metabolism, namely intact PTH (iPTH), bone-specific alkaline phosphatase (bAP), and osteocalcin, for the correlations with bone histomorphometric parameters. Serum PYD levels (mean +/- SD) were significantly higher in dialysis patients than in normal individuals, 90.6 +/- 99.6 nM versus 1.9 +/- 0.4 nM, respectively. Patients with high turnover bone disease had significantly higher serum PYD levels than patients with normal or low bone turnover, 108.8 +/- 108.0 nM versus 34.1 +/- 12.8 nM, respectively. Serum PYD levels were positively correlated with bone resorption parameters including osteoclast surface (r = 0.59, p < 0.0001) and osteoclast number/mm2 (r = 0.61, p < 0.0001), and also with bone formation parameters, osteoblast surface (r = 0.43, p < 0.008), double-labeled surface (r = 0.81, p < 0.001), and BFR (r = 0.91, p < 0.0001). The BFR was better correlated with serum PYD levels than with either serum iPTH or osteocalcin concentrations. However, correlation with serum bAP was comparable.(ABSTRACT TRUNCATED AT 250 WORDS)
Link: http://www.ncbi.nlm.nih.gov/pubmed/7572317?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=2