Response to: Mansour J et al. (2007) Optimal paricalcitol starting dose for parathyroid hormone suppression in secondary hyperparathyroidism. Nat Clin Pract Nephrol doi:10.1038/ncpneph0442

Original article: Bushinsky DA (2007) Optimal paricalcitol starting dose for parathyroid hormone suppression in secondary hyperparathyroidism. Nat Clin Pract Nephrol 3: 12–13 doi:10.1038/ncpneph0363

I would like to thank Mansour and colleagues for agreeing that rigorous clinical trials, with hard outcomes such as vascular calcification, cardiovascular events and mortality, are necessary to determine the optimal treatment approach to the disorders of divalent ion metabolism in patients on dialysis. They essentially make two points in their response to my Practice Point. The first is that such patients should be substrate-replete with respect to vitamin D and the second is that cinacalcet should be used with calcium carbonate and not with low doses of paricalcitol or calcitriol (1,25[OH]2-vitamin D).

It is evident that everyone—not only patients with chronic kidney disease (CKD) stages 3–4, but individuals with normal renal function and those without any renal function—should be replete with all vitamins including vitamin D. As I said in the Practice Point, “As a result of the many nonmineral-related actions of vitamin D3, physiologic repletion of this hormone is widely considered prudent”. Vitamins are essential to normal health. The British Navy prevented scurvy with oranges, lemons and limes long before the essential nutrient vitamin C was isolated. Rickets is prevented by provision of vitamin D. Many individuals are vitamin D-deficient and this essential nutrient should be replenished with either cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2), depending on availability. Whether the target calcidiol (25OH-vitamin D) level should be 100 nmol/l (40 ng/ml), as suggested by current guidelines for patients with stage 3–4 CKD,1 or higher, is currently not known. Identification of the optimal target level should, however, be based on rigorous, peer-reviewed, published clinical trials, rather than on unpublished personal communications as suggested by Mansour and colleagues.

Mansour et al. propose that cinacalcet should be used with calcium carbonate as a phosphate binder. Cinacalcet sensitizes the calcium receptor to calcium, resulting in a suppression of parathyroid hormone (PTH) secretion at any level of serum calcium; the curve describing the relationship between calcium level and PTH secretion is shifted to the left2. Should we attempt to raise the resultant reduction in serum calcium using calcium carbonate? I think not. Calcium loading, using ample amounts of calcium-based phosphate binders, raises the probability of inducing vascular calcification.3 A fraction of dietary calcium is always absorbed, more if the patients are also given 1,25(OH)2-vitamin D3 or analogs.4 As there is no renal egress for this mineral, it must ultimately be deposited in bone or, if all bone matrix is mineralized, in the vascular tissue. Mansour et al. point to a letter that they wrote to Kidney International comparing two different non-randomized studies that used different amounts of cinacalcet and sevelamer, and were carried out at different institutions by different investigators. They claim that the “only possible explanation” for the difference in serum phosphate reduction between these trials was the introduction of calcitrol or paricalcitol in one study. Again, proposed treatment algorithms should be based on rigorous peer-reviewed clinical trials and not on comparisons of disparate studies.

With careful study over time we are determining optimal treatment strategies in patients with CKD, virtually all of whom have disorders of divalent ion metabolism. Opinions, based on personal communications and letters to the editor, have little role this process.