Oral calcium, sevelamer and vascular calcification in uraemic patients

Albert Fournier, Claire Presne, Roxana Oprisiu and Tarek Sadek

Hôpital Sud Service de Néphrologie F-80054 Amiens Cedex 1France Email: fournier.albert{at}chu-amiens.fr

Sir,

We have greatly appreciated the excellent, challenging review by Coladonato et al. [1] of the issue relating oral calcium load to artery calcifications and cardiovascular complications. We would like to add scientific works, which do not support this link, and stress shortcomings of the protocol design of the recently published ‘Treat to goal’ study [2] aimed at proving a causal relationship between oral calcium load and cardiovascular damage.

As Coladonato et al. [1] already have stressed the weaknesses of cross-sectional studies, we wish to focus on three longitudinal, observational studies. Renaud et al. [3] assessed for 3 years the extension of calcifications in the abdominal aorta and iliac arteries. They showed that it was independently associated primarily with age, male gender, blood pressure, and plasma triglyceride and glucose levels whereas the link with plasma concentrations of calcium and phosphate was borderline and not at all significant with the dose of CaCO3. In the study by Goldsmith et al. [4] progression of vascular calcification was also related primarily to age and blood pressure, and also to plasma phosphate, calcitriol and ferritin levels, but paradoxically there was a negative correlation with plasma calcium. Furthermore this study showed that surgical treatment of hyperparathyroidism was followed by less extensive vascular calcification than medical parathyroidectomy by more aggressive calcitriol therapy. The third study by Bonifacio et al. [5] challenges the bad prognostic significance of coronary calcifications in haemodialysis patients after percutaneous dilatation of coronary artery stenosis. Long-term morbidity and mortality were actually better in patients with calcifications, the apparent paradox being explained by a more severe dyslipidaemia in those without calcifications.

As regards the shortcomings of the ‘Treat to goal’ study design, it is important to stress that the plasma parathyroid hormone (PTH) levels actually obtained were in the targeted range (150–300 pg/ml) for the Renagel® group, but below this range for the patients in the calcium group, this PTH oversuppression possibly contributed to the higher incidence of hypercalcaemia (33 vs 7%) and therefore to a higher risk of soft tissue calcification [6]. It is interesting to point out that the 7% incidence of hypercalcaemia observed with Renagel®+1{alpha}OH vitamin D was comparable with that observed in our trial comparing CaCO3 with calcium acetate in patients not taking 1{alpha}OH vitamin D, as this latter was only 8%. Furthermore, this incidence was comparable with both calcium salts [7] and not lower with calcium acetate (in contrast to the suggestion of Coladonato et al. [1]), in spite of its twice-lower dose when expressed in calcium element.

With regard the oversuppression of PTH in the calcium group of the ‘Treat to goal’ study, it questions the necessity of administering 1{alpha}OH vitamin D to this group. In such patients with moderate hyperparathyroidism, Indridason and Quarles [8] clearly demonstrated that increasing oral CaCO3 intake from 5 to 15 g daily was as effective as daily oral or intermittent intravenous (i.v.) calcitriol in maintaining PTH between 200 and 100 pg/ml at a comparable serum calcium of 9.0–9.5 mg/dl, with the distinct advantage of maintaining serum phosphate at 3.5 mg/dl instead of 5.0 mg/dl in the calcitriol group, while aluminum hydroxide was needed in the two calcitriol groups, exposing both to long-term aluminum toxicity and higher risk of soft tissue calcifications.

As dyslipidaemia is a recognized risk factor for coronary artery calcification [9] the fact that sevelamer significantly improved uraemic dyslipidaemia [10] gives a distinct advantage to this phosphate binder over CaCO3 in the prevention of vascular calcium overload. However the results of the ‘Treat to goal’ study cannot be readily used to demonstrate the claimed vascular toxicity of oral calcium per se. To solve this issue, which has an obvious economic impact for public health expenditures, a cost-effectiveness study of the prevention not only of vascular calcifications but of all-cause cardiovascular events should therefore be performed to prove the claimed superiority of sevelamer+1{alpha}OH vitamin D derivatives over high doses of CaCO3 (used as phosphate binder in association with physiological repletion in native vitamin D) and associated to a statin to obtain a comparable control of dyslipidaemia. The present monthly cost estimation for a combination of sevelamer (Renagel®)+alfacalcidol is 150 Euros whereas that for calcium+statin it is only 52 Euros. Therefore, 100 Euros is the price to pay for a still unknown reduction of cardiovascular morbidity and mortality with sevelamer±alfacalcidol in uraemic patients.

As blood pressure [11] and oestrogen status are of particular importance in the incidence of vascular calcifications, the design of such a study should also include a comparable control of blood pressure and oestrogen status with comparable medications in each study group.

References

  1. Coladonato JA, Szczech LA, Friedman EA, Owen WF, Jr. Does calcium kill ESRD patients–the skeptic's perspective. Nephrol Dial Transplant2002; 17:229–232[Free Full Text]
  2. Chertow GM, Burke SK, Raggi P for the Treat to Goal Working Group. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int2002; 62:245–252[ISI][Medline]
  3. Renaud H, Atik A, Herve M. Evaluation of vascular calcinosis risk factors in patients on chronic hemodialysis: lack of influence of calcium carbonate. Nephron1988; 48:28–32[ISI][Medline]
  4. Goldsmith DJ, Covic A, Sambrook PA, Ackrill P. Vascular calcification in long-term haemodialysis patients in a single unit: a retrospective analysis. Nephron1997; 77:37–43[ISI][Medline]
  5. Bonifacio D, Malineni K, Kadakia R, Soman S, Sandberg K, Mc Cullough P. Coronary calcification and cardiac events after percutaneous intervention in dialysis patients. J Cardiovasc Risk2001; 8:133–137[ISI][Medline]
  6. Drueke TB. Foreword: extraskeletal calcifications in patients with chronic renal failure. Nephrol Dial Transplant2002; 17:330–331[Free Full Text]
  7. Ben Hamida F, El Esper I, Compagnon M, Moriniere P, Fournier A. Long-term (6 months) cross-over comparison of calcium acetate with calcium carbonate as phosphate binder. Nephron1993; 63:258–262[ISI][Medline]
  8. Indridason OS, Quarles LD. Comparison of treatments for mild secondary hyperparathyroidism in hemodialysis patients. Durham Renal Osteodystrophy Study Group. Kidney Int2000; 57:282–292[ISI][Medline]
  9. Tamashiro M, Iseki K, Sunagawa O et al. Significant association between the progression of coronary artery calcification and dyslipidemia in patients on chronic hemodialysis. Am J Kidney Dis2001; 38:64–69[ISI][Medline]
  10. Chertow G, Burke S, Dillon M, Slatopolsky E, for the Renagel study group. Long term effects of sevelamer hydrochloride on the calcium phosphate product and lipid profile on haemodialysis patients. Nephrol Dial Transplant1999; 14:2907–2914[Abstract/Free Full Text]
  11. Christian RC, Harrington S, Edwards WD, Oberg AL, Fitzpatrick LA. Estrogen status correlates with the calcium content of coronary atherosclerotic plaques in women. J Clin Endocrinol Metab2002; 87:1062–1067[Abstract/Free Full Text]




This Article
Extract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Fournier, A.
Articles by Sadek, T.
PubMed
PubMed Citation
Articles by Fournier, A.
Articles by Sadek, T.