NDT Advance Access originally published online on October 12, 2005
Nephrology Dialysis Transplantation 2006 21(2):551-552; doi:10.1093/ndt/gfi200
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Cinacalcet and vascular calcifications induced by calcitriol
Email: fournier.albert{at}chu-amiens.frSir,
We read with great interest the article by Henley et al. [1] showing that cinacalcet could not prevent vascular calcifications induced by calcitriol in uraemic rats and would like to make the following comments:
- This inefficiency might be explained by the stability of the calcium x phosphate (Ca x PO4) product because the decrease in serum calcium (SCa) was compensated by an increase in SPO4. Indeed at the end of the study, the mean SPO4 of the three measurements (before and 4–24 hours after the dose) was 1.4 mg/dl (29%) higher when cinacalcet was compared with vehicle and 1.9 mg/dl (23%) higher when cinacalcet + calcitriol was compared with calcitriol alone.
- This hyperphosphataemic effect of cinacalcet in uraemic rats has already been reported with the first generation calcimimetic NPS558 [2] and is in complete agreement with the mirror image of the trade off theory of secondary hyperparathyroidism in uraemia developed by Slatopolsky and Bricker [3]: hyperparathyroidism is the price the organism pays to eliminate phosphate retention induced by the reduction of its glomerular filtration.
- These experimental results do not contradict the decrease in SPO4 reported in dialysis patients receiving cinacalcet [4]. This decrease was, however, mild (7%) when 1
OH vitamin D was stable and almost twice smaller when 1OH vitamin D was increased [5]. This difference can probably be explained by the fact that when vitamin D is increased to correct cinacalcet-induced hypocalcaemia, PO4 absorption is increased, whereas when CaCO3 is used instead, this latter complexes phosphate in the gut and decreases SPO4.
- These deleterious effects of calcitriol in uraemic rats and patients contrast with beneficial effects of an increased oral calcium-load:
- In uraemic rats, high calcium diet alone has been shown to decrease mortality in association with a lower SPO4 and a decrease in proteinuria and blood pressure associated with a lower expression of the AT1-receptor of angiotensin II [6]. In uraemic mice with ApoE gene deletion-induced atherosclerosis, high calcium is also quite effective in decreasing aortic calcifications [7].
- In dialysis patients, never exposed to aluminium, high CaCO3 dose (6–9 g per day taken as phosphate binder ie at 2.4–3.6 g of elemental calcium), without 1OH vitamin D, but with calcidiol repletion and a dialysate calcium concentration of 1.5 mmol/l (not inducing negative per-dialytic calcium balance), a good control of hyperparathyroidism can be obtained (usual PTH<220 pg/ml in two third of the patients) without hypercalcaemia nor hyperphosphoraemia. This results in a good preservation of bone mineral density (BMD), especially of the cortical bone, without any inverse correlation between BMD and vascular calcification, as has been reported in dialysis patients using 1OH-vitamin D [8]. The only independent risk factors for vascular calcifications were age and duration on dialysis, whereas phosphocalcic, plasmatic and therapeutical parameters were in no way correlated [9].
- In uraemic rats, high calcium diet alone has been shown to decrease mortality in association with a lower SPO4 and a decrease in proteinuria and blood pressure associated with a lower expression of the AT1-receptor of angiotensin II [6]. In uraemic mice with ApoE gene deletion-induced atherosclerosis, high calcium is also quite effective in decreasing aortic calcifications [7].
- Therefore we think that these experimental and clinical data should lead to revision of certain therapeutical recommendations made by the NKF K/DOQI in 2003 before cinacalcet was on the market [10].
- To definitively limit the use of 1OH vitamin D in uraemic patients and to rely mainly on calcidiol repletion (
30 ng/ml) to take advantage of the multiple health benefits given by the sunshine vitamin [11]. This approach should be recommended, not only for the CKD grade 3–4 patients (as is already done by NFK/K/DOQI of 2003), but also for dialysis patients.
- To use 1OH vitamin D only with non-calcic-phosphate binders in order to prevent a SPO4 increase above 1.50 mmol/l in predialyis patients and >1.60 mmol/l in the dialysis patients.
- To give priority to Ca oral phosphate binders over 1OH vitamin D to correct the cinacalcet-induced hypocalcemia both in dialysis and predialysis patients.
- To use cinacalcet in predialysis patients (repleted in calcidiol) to control their hyperparathyroidism only when their SPO4 is controlled by Ca-phosphate binder, and their SCa is increasing above 2.37 mmol/l, the upper limit of the optimal range suggested by the last USRD study, since it pointed to a significant increase in mortality risk above this threshold [4].
- To definitively limit the use of 1
Conflict of interest statement. None declared.
1 Department of Nephrology2 INSERM-ERI12-CHU Amiens-Picardie University
References
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[Abstract/Free Full Text] - Fox J, Lowe S, Petty B, Nemeth E. NPS R-568: a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and calcium. J Pharmacol Exp Ther 1999; 290: 473–479
[Abstract/Free Full Text] - Slatopolsky E, Bricker NS. The role of phosphorus restriction in the prevention of secondary hyperparathyroidism in chronic renal disease. Kidney Int 1973; 4: 141–145[Web of Science][Medline]
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- Phan O, Ivanovski O, Nguyen-Khoa T et al. Sevelamer prevents accelerated atherosclerosis in apolipoprotein E deficient (apoE–/–) mice with chronic renal failure (CRF) Abstract 5. J Am Soc Nephrol 2004; 15: 275A (Poster FPO962)
- Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC. Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 1996; 27: 394–401[Web of Science][Medline]
- Fournier A, Said S, Ghazali A et al. The clinical significance of adynamic bone disease in uremia. In: Grünfeld JP ed., Advances in Nephrology Year-Book. St Louis: Mosby, 1997; 27: 131–166
- KDOQI: National Kidney Foundation KDOQI (Kidney Disease Outcomes Quality Initiative). Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42 [Suppl 13]: S1–S201
- Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 2004; 80: 1678S–1688S
[Abstract/Free Full Text]
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