CaSR and calcimimetics

Dr. Martin Pollak, USA

The genetic pathways of two diseases that were identified decades ago—familial benign hypercalcemia (FBH) and familial hypocalciuric hypercalcemia (FHH)—have now been linked to mutations in the calcium-sensing receptor (CaSR) gene, thought to control and regulate calcium levels.


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CaSR has been found in numerous tissues, including parathyroid glands, kidney, and bone, and is widely expressed in tissues and cell types without known involvement in mineral ion metabolism. The role of CaSR in these tissues is not clear; however, CaSR-knockout mice are small and sick (Figure 2).

Figure 2: Mice lacking CaSR behave like humans lacking CaSR.
Figure 2: Mice lacking CaSR behave like humans lacking CaSR.

CaSR are now being considered as therapeutic targets for the following two reasons: 

  1. Treatment of various disorders of calcium homeostasis/metabolism is inadequate (eg, in hemodialysis patients, treatment with vitamin D derivatives can control parathyroid hormone but can lead to hypercalcemia and hyperphosphatemia).
  2. Other potential disease states might also be amenable to treatment by activation or inactivation of CaSR : kidney stones, osteoporosis,primary hyperparathyroidism (PHPT), etc.

Calcimimetics are ligands that act on the CaSR to mimic or potentiate the effects of calcium. There are two types of calcimimetics, distinguished by molecular mechanism of action:

  • Type I: conventional agonists: depress parathyroid hormone secretion even in the absence of extracellular calcium.
  • Type II: Positive allosteric modulators: increase the sensitivity of the CaSR to activation by extracellular calcium.

Cinacalcet, a Type II calcimimetic, is the only currently available calcimimetic approved by the FDA for SHPT in patients with CKD undergoing hemodialysis and for severe hypercalcemia in parathyroid carcinoma. Cinacalcet treatment results in long-term, sustained reduction in serum calcium levels in PHPT patients and reduces parathyroid hormone and calcium/phosphate product levels in patients with SHPT; in pivotal trials, most patients were also on vitamin D and a phosphate binder.

Cinacalcet is only approved in stage 5 CKD, not stages 3 and 4, where it has been shown to increase hypocalcemia and hyperphosphatemia, possibly caused by parathyroid hormone; this indicates that care must be taken when altering the mechanisms that regulate the calcium receptor.


Calcium myths and calcium needs

Professor David Bushinsky, USA

Professor Bushinsky presented the timescales involved in the derangement of mineral metabolism in CKD. As kidneys fail, parathyroid hormone increases, levels of vitamin D decrease, and levels of FGF-23 increase substantially; these changes can occur very early in the course of CKD, whereas calcium and phosphate are tightly controlled until quite late in the disease progression.

Increases in phosphate and FGF-23 have both been shown to be independent predictors of mortality in CKD patients, and calcium and phosphate increase vascular calcification in CKD patients, which in itself predicts greater mortality.

Figure 3: Model of calcium metabolism.
Figure 3: Model of calcium metabolism.

Using the model of calcium metabolism (Figure 3) in a healthy person, the 20 mmoles of calcium ingested is excreted via the feces or urine, with the process being buffered by the bone and passing through the extracellular fluid (ECF).

However, as CKD progresses, the amount of calcium excreted by the kidneys decreases to zero, which means that the critical parameter in calcium homeostasis in the CKD patient is the ECF concentration:

  • Net calcium influx into the ECF promotes calcium retention and may promote vascular calcification.
  • Net calcium efflux from the ECF may worsen SHPT and decrease bone mass.

Parameters that can influence calcium balance in CKD patients include hemodialysis, dietary calcium content, calcium-based phosphate binders, and vitamin D, making the determination of calcium balance in CKD patients difficult. Professor Bushinsky generated assumptions for calculating balance as follows:

  1. Hemodialysis is performed 3 times/week
  2. Hemodialysis bath calcium = 1.25 mM (2.5 mEq/L)
  3. Net calcium flux during hemodialysis only if there is ultrafiltration
  4. 3 L of ultrafiltration during each hemodialysis treatment
  5. Gastrointestinal calcium absorption is 19% of dietary calcium without activated vitamin D and 25% of dietary calcium with activated vitamin D, regardless of dose
  6. Calcium secretion into the stool = 3.6 mmoles/day
  7. All activated vitamin D preparations increase intestinal calcium absorption equally
  8. All calcium from food and binders will be absorbed equally
  9. Calcium loss from sweat = 1.6 mmoles/day
  10. Urine calcium = 0
  11. No net calcium flux relative to bone

Using these assumptions, a patient ingesting 1500 mg calcium/day with no vitamin D supplementation would accumulate 117 mmoles calcium per year. If the same amount of calcium was ingested with activated vitamin D, this would mean an accumulation of 920 mmoles/year, which is equivalent to 2-3% of the total calcium in the bone.

For a calcium intake of 2000 mg/day these values increase to 984 mmoles/year and 2,046 mmoles/ year, respectively. This final accumulation of calcium is equivalent to 6-7% of bone calcium; therefore, the amount of retained calcium in a CKD patient is significant on a yearly basis. Further studies are warranted to determine the validity of the assumptions used in this model and, subsequently, the fate of retained calcium.

The forum discussed the fact that hemodialysis would be more beneficial if it was carried out 6 times per week as opposed to the standard 4 hours 3 times per week; the need for phosphate binders would greatly decrease. Use of the model of calcium metabolism to investigate the effects of different types of activated vitamin D on calcium absorption was also discussed, as was the effect of a calcimimetic in this model.

Although cinacalcet was shown to reduce calcium absorption in this model, the reduction was not statistically significant. Caution was advised regarding introduction of calcium-raising measures to counter excessive hypocalcemia in hemodialysis patients, as patients would then be using large amounts of 1,25 vitamin D and calcium-based phosphate binders, which may make the situation worse. Serum calcium is also not a good measure of calcium physiology because it only represents a small percentage; fluxes into and out of extracellular fluid affect vascular calcification and bone health far more.


The role of phosphate in cardiovascular risks in the general population and in CKD

Professor Keith Hruska, USA

Increased serum phosphate levels have been shown to be related to the increased risk of cardiovascular disease in otherwise healthy people, and in patients with CKD requiring or not requiring hemodialysis. Vascular calcification is prevalent in CKD and is composed of both plaque (neointimal) and medial calcification. Vascular smooth muscle cells are stimulated by hyperphosphatemia to express genes associated with bone formation and start to lay down mineral deposits. Medial vascular calcification leads to vessel stiffness, which can result in left ventricular hypertrophy and cardiac events.

Data from observational studies (the prospective CARDIA study and the population-based crosssectional MESA study) show that increased serum phosphate levels are associated with increased arterial stiffness in healthy young adults (CARDIA) and in middleaged patients with normal kidney function or mild-to-moderate kidney disease (MESA).

In a mouse model of CKD and atherosclerosis, administration of phosphate binders and bone morphogenetic protein-7 (BMP-7) corrected hyperphosphatemia (Figure 4) and osteodystrophy and reversed vascular calcification by improving bone turnover and increasing phosphate deposition within bone.

In this same animal model, sevelamer carbonate reduced serum phosphate levels, reversed adynamic bone disease and prevented aortic calcification and cardiac hypertrophy. The mechanism by which phosphate causes vascular calcification seems to be via expression of osterix and other bone transcription factors, which promote vascular mineralization.

Figure 4: Hyperphosphatemia is central to failure of a multi-organ system in CKD.
Figure 4: Hyperphosphatemia is central to failure of a multi-organ system in CKD.

The effects of reduced phosphate levels have been investigated in a prospective cohort study of 10,044 patients initiating hemodialysis in 1056 centers from years 2004 to 2005 (ArMORR).

Increasing serum phosphate levels were associated with decreased survival, but this was ameliorated in patients who received any phosphate binder for their first 3 months on hemodialysis. Serum phosphate is a cardiovascular risk factor in CKD and the general population.

Furthermore, translational studies of human primary aortic cells in vitro have demonstrated that hyperphosphatemia stimulates vascular calcification by inducing osteoblastic gene expression in the aorta; correction of hyperphosphatemia has been shown to decrease vascular calcification in humans; however, the role of serum phosphate as a validated cardiovascular risk factor in CKD needs to be confirmed.

Questions arising from this presentation included the role of collagen as a co-risk factor for vascular calcification and the role of the phosphate transporter piT-1; phosphate could be used as a marker of vascular calcification in the same way blood pressure is used to predict cardiovascular mortality in the general population. RCTs are needed to validate phosphate as a cardiovascular risk factor.