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NDT Advance Access originally published online on August 25, 2006
Nephrology Dialysis Transplantation 2006 21(10):2987-2989; doi:10.1093/ndt/gfl370
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Current treatment options in secondary renal hyperparathyroidism

Email: Fournier.Albert{at}chu-amiens.fr

Sir,

We read with interest the editorial comment by H. Reichel on the current treatment options in secondary renal hyperparathyroidism (SRHPT) and we totally agree with his conclusion that cinacalcet offers a fundamentally different approach to SRHPT therapy when compared with ‘active’ vitamin D derivative-based approach. However, we would like to make a few comments and raise the issue of the cost-effectiveness of this new treatment.

The first comment concerns the current justification of the so called ‘active’ vitamin D metabolites. This adjective is actually a misnomer, since it is used for designating 1{alpha} OH vitamin D derivatives, which are the most potent vitamin D derivatives to increase intestinal absorption of calcium and phosphate and the serum concentrations of these divalent ions, but not necessarily the most ‘efficace’ at suppressing parathyroid hormone (PTH) when used at physiological dose. Recently, the Ritter and group [1] showed, on bovine parathyroid cell culture that calcidiol at the physiological concentration of 40 ng/ml was as effective as maximal PTH-suppressing calcitriol dose.

Two reasons may explain this observation:

  1. physiological systemic concentrations of calcidiol are 103 times greater than those of calcitriol;
  2. parathyroid cells have a megalin receptor which allows the introduction of calcidiol and its in situ transformation into calcitriol, thanks to a local mitochondrial 25 OH vitamin D-1{alpha} hydroxylase [2].

Furthermore, the in situ synthesis of calcitriol has also been evidenced in the monocytes, macrophages [3] and in the vascular smooth muscle cells [4]. Even though uraemia induces a decrease of 25 OH vitamin D uptake by these cells, the production of calcitriol can be normalized by just increasing 25 OH vitamin D levels below the hypercalcaemic threshold [3].

This local production of calcitriol in various cells explains the possibility of these cells to exert physiologically beneficial effects on PTH, immunomodulation and vascular remodelling even in uraemic patients in order to compensate for the non-optimal calcitriol systemic levels in these patients. Thus, the most physiological and safest vitamin D compound to give to these patients may actually be native vitamin D or 25 OH vitamin D, rather than 1{alpha} OH vitamin D derivatives, specially when given intermittently by intravenous route, which induces unphysiological systemic peaks responsible within a year for a significant increase of SCa (+6.5 and +8%) and SPO4 (+12 and 14%) with intravenous paricalcitol and calcitriol, respectively [5].

The fact that in American dialysis cohorts systematic injection of paricalcitol or calcitriol gave some survival benefit compared with no treatment, may be explained by the fact that, according to Kidney Disease outcome Quality Initiative (K/DOQI), American dialysis patients—in contrast to chronic kidney disease (CKD) stage 3–4 patients—should not be repleted in native vitamin D, so that their serum calcidiol is actually <15 ng/ml in 87% and <5 ng/ml in 5% of these patients [6], i.e. far from the physiological repletion range level (≥30 mg/ml) recommended by the K/DOQI.

Since epidemiological studies have shown that vitamin D repletion is associated with lower cardiovascular mortality and lower prevalence of diabetes, immunological, cancerous and infectious diseases [7], whereas its depletion in uraemic patients is associated with heart failure and inflammatory state [8], the partial correction of this vitamin D depletion by intravenous paricalcitol or calcitriol, may explain the better clinical outcome of the patients who received these drugs. The fact that mortality was, however, 4% lower in the patients treated with paricalcitol, compared with those treated with calcitriol, merely suggests that the beneficial effect of this partial vitamin D repletion has been lower with calcitriol, because of its greater hypercalcaemic and hyperphosphataemic effects. We, therefore, suggest that the benefit would have still been greater, if just native or 25 OH vitamin D had been given to restore S calcidiol levels at ≥30 ng/ml, as recommended by the K/DOQI for pre-dialysis CKD patients. Only a placebo controlled trial with these drugs in vitamin D repleted dialysis patients can establish their intrinsic capacity to increase survival.

The second comment addresses the comparability issue regarding the hypercalcaemic effect of calcium carbonate (CaCO3) and calcium acetate. Reichel appropriately reports the work of Mai et al. showing, in a one-day PO4/calcium intestinal absorption study (by intestinal cleansing) performed in a few dialysis patients, that Ca acetate complexed phosphate more efficiently for the same calcium absorption. However, the clinical relevance of this study has been questioned by two independent long-term cross-over studies [9,10] comparing the control of hyperphosphataemia by either CaCO3 or Ca acetate, while the dose of the latter (expressed in elemental calcium), was twice as low: both drugs controlled hyperphosphataemia adequately but with the same risk of hypercalcaemia. Thus, these clinical studies rather suggest that, for the same dose of elemental calcium, the risk of hypercalcaemia with Ca acetate is actually twice of that with CaCO3. The reason for this paradox may be that on longer term and in more physiological conditions for intestinal absorption, the greater solubility of Ca acetate than of CaCO3 at alkaline duodeno–jejunum pH leads to a greater bioavailability of calcium, not only for complexing PO4, but also for being absorbed. This leads us to suggest that since, in the USA, only Ca acetate has the FDA approval as a phosphate binder, the K/DOQI recommendation of using a daily dose of Ca oral phosphate binder (Ca OPB) <1.5 g elemental calcium is valid only for Ca acetate, and that the double dose should be recommended in other countries in which CaCO3 is approved as phosphate binder.

Thirdly, regarding the algorithm for clinical use of cinacalcet proposed by Cunningham and Reichel, we would like to challenge its proposition to use 1{alpha} OH vitamin D instead of a higher dose of Ca OPB to correct and/or prevent SCa decrease induced by cinacalcet.

The comparison of two earlier trials with cinacalcet titrated up to 50 mg [11] or 100 mg [12], showed that while the baseline and suppressed PTH levels were comparable, the SPO4 was significantly decreased by 7% with the lower dose but not with the twice higher cinacalcet dose. The only explanation for this discrepancy was the greater number of patients put on calcitriol or paricalcitol in the second study. Indeed 1{alpha} OH vitamin D derivatives are less PTH-suppressive than Ca OPB, since their hypercalcaemic effect is counterbalanced by their hyperphosphataemic effect, so that they suppress PTH synthesis mainly by blunting the transcription of the prepro-PTH gene. Furthermore they increase fibroblast growth factor 23 (FGF23) which down-regulates the 25 OH vitamin D-1{alpha} hydroxylase. In contrast, Ca OPB suppresses PTH by both increasing SCa and decreasing SPO4 and FGF23 which leads, respectively, to an increased expression of the calcium receptor [13] and to an up-regulation of the 25 OH-1{alpha} hydroxylase [14].

Finally, we would like to address the issue of the optimal calcium concentration in the dialysate. According to K/DOQI, when PTH is ≥300 pg and 1{alpha} OH vitamin D use is considered, a low-dialysate calcium <1.5 mmol/l is recommended. Since for more than 30 years [15] these concentrations have been known to stimulate PTH and exacerbate radiological osteitis fibrosa, these two measures are obviously not very cost-effective, especially when cinacalcet use is considered. In this case, we rather propose to initially use a 1.5 mmol/l calcium concentration (giving a perdialytic calcium balance approximately neutral) and, when Ca OPB increases (without any limitation except an albumin-corrected SCa >2.37 mmol/l) fails to prevent the cinacalcet-induced hypocalcaemia (<2.2 mmol/l), to further increase the calcium concentration in the bath. As shown recently, such dialysate concentration can bring S PTH levels above 2000 pg/mml back to <500 within 6 months, while the cinacalcet dose is only 30 mg [16].

Thus, correcting cinacalcet-induced hypocalcaemia by a higher dose of Ca OPB or higher dialysate calcium concentration would remarkedly increase the cost-effectiveness of this drug.

Jean-François Bonne, Jeanette Mansour, Irina Shahapuni Philippe Moriniere and Albert Fournier

Service de Néphrologie
CHU Amiens
France

References

  1. Ritter CS, Armbrecht HJ, Slatopolsky E, Brown AJ. (2005) 25 hydroxyvitamin D3 suppresses PTH synthesis and secretion by cultured bovine parathyroid cells: potential role for intracrine1.25(OH)2 D3. J Am Soc Nephrol 16: : Poster SA PO 889.
  2. Segersten U, Correa P, Hewison M, et al. (2002) 25-hydroxyvitamin D(3)-1alpha-hydroxylase expression in normal and pathological parathyroid glands. J Clin Endocrinol Metab 87:2967–2972.[Abstract/Free Full Text]
  3. Gallieni M, Kamimura S, Ahmed A, et al. (1995) Kinetics of monocyte 1 alpha-hydroxylase in renal failure. Am J Physiol 268:F746–F753.[Medline]
  4. Somjen D, Weisman Y, Kohen F, et al. (2005) 25-hydroxyvitamin D3-1alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation 111:1666–1671.[Abstract/Free Full Text]
  5. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R. (2003) Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349:446–456.[Abstract/Free Full Text]
  6. Finn W. (2005) Evidence of vitamin D and vitamin K deficiency in patients with ESRD. J Am Soc Nephrol 16:755A (SA-PO910).
  7. Holick MF. (2004) Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr 80 [Suppl 6]:S1678–S1688.
  8. Levin A and Li YC. (2005) Vitamin D and its analogues: do they protect against cardiovascular disease in patients with kidney disease? Kidney Int 68:1973–1981.[CrossRef][ISI][Medline]
  9. Ben Hamida F, El Esper I, Compagnon M, Moriniere P, Fournier A. (1993) Long-term (6 months) cross-over comparison of calcium acetate with calcium carbonate as phosphate-binder. Nephron 63:258–262.[ISI][Medline]
  10. Delmez JA, Tindira CA, Windus DW, et al. (1992) Calcium acetate as a phosphorus binder in hemodialysis patients. J Am Soc Nephrol 3:96–102.[Abstract]
  11. Lindberg JS, Moe SM, Goodman WG, et al. (2003) The calcimimetic AMG 073 reduces parathyroid hormone and calcium x phosphorus in secondary hyperparathyroidism. Kidney Int 63:248–254.[CrossRef][ISI][Medline]
  12. Quarles LD, Sherrard DJ, Adler S, et al. (2003) The calcimimetic AMG 073 as a potential treatment for secondary hyperparathyroidism of end-stage renal disease. J Am Soc Nephrol 14:575–583.[Abstract/Free Full Text]
  13. Ritter CS, Martin DR, Lu Y, Slatopolsky E, Brown AJ. (2002) Reversal of secondary hyperparathyroidism by phosphate restriction restores parathyroid calcium-sensing receptor expression and function. J Bone Miner Res 17:2206–2213.[CrossRef][ISI][Medline]
  14. Nagano N, Miyata S, Abe M, et al. (2006) Effect of manipulating serum phosphorus with phosphate binder on circulating PTH and FGF23 in renal failure rats. Kidney Int 69:531–537.[CrossRef][ISI][Medline]
  15. Fournier AE, Arnaud CD, Johnson WJ, Taylor WF, Goldsmith RS. (1971) Etiology of hyperparathyroidism and bone disease during chronic hemodialysis. II. Factors affecting serum immunoreactive parathyroid hormone. J Clin Invest 50:599–605.[ISI][Medline]
  16. Touam M, Menoyo V, Attaf D, Thebaud HE, Drueke TB. (2005) High dialysate calcium may improve the efficacy of calcimimetic treatment in hemodialysis patients with severe secondary hyperparathyroidism. Kidney Int 67: : 2005; author reply 2065–2066.

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