Kettler_EU_Renal_version2 9/7/07 10:14 am Page 26
Phosphorus Control
properties such as binding cholesterol, uraemic toxins or other their respective cohorts and will yield important results within the next
pro-inflammatory factors three years.
Cincalcet and Other ‘Suspects’ Nicotinamide, originally prescribed in the treatment of dyslipidaemias
Cinacalcet, the allosteric modulator of the Ca-sensing receptor (CaSR), due to its low-density lipoprotein (LDL)-lowering and high-density
lowers both serum Ca and P concentrations in addition to suppressing lipoprotein (HDL)-increasing properties, is an inhibitor of active
immunoreactive PTH (iPTH) secretion.
23
This highly reproducible and transcellular P absorption. This mechanism of action requires
persistent effect may be due to an improved bone turnover and thus appropriate pre-clinical and clinical trials in order to evaluate the
an increased ion uptake into the bone, but potentially also by effects potency and the tolerability of the drug compared to the available
on the ion efflux from the intracellular into the extracellular treatment options.
26
Last but not least, one should not forget about the
compartment. Cinacalcet also suppresses parathyroid hyperplasia value of increasing the dialysis dose, either by increasing the length of
when administered and prevents calcitriol-induced vascular each session (e.g. 3x8h per week, ‘nocturnal dialysis’) or frequency (e.g.
calcifications in experimental models.
24,25
The new developments 6x3h per week), both of which will normalise phosphate levels in most
concerning the value of cinacalcet in the current treatment of patients if on a reasonable diet.
27
Conclusion
The missing pieces in this therapeutic
According to epidemiological data, hyperphosphataemia appears to
be one of the key threats to the event-free survival of dialysis, and
puzzle are prospective, hard-outcome
potentially to a considerable part of CKD stage 3 and 4 patients. The
data showing clear-cut superiority of
mainstay of therapy is the use of P binders, while management of
hyperphosphataemia by balanced diets should be used in conjunction.
the available treatment options, while
Combinations of the different P binders may improve P control and
sevelamer hydrochloride probably still
consequently limit side effects (e.g., Ca load, gastrointestinal complaints).
The missing pieces in this therapeutic puzzle are prospective, hard-
has the most solid dataset available.
outcome data showing clear-cut superiority of the available treatment
options, while SEV probably still has the most solid dataset available.
However, it must be kept in mind that all data that demonstrated harmful
secondary hyperparathyroidism and CKD-associated mineral disorders effects of hyperphosphataemia are obtained from observational studies.
are related to the launch of two large, prospective, randomised, For example, there is no prospective randomised, controlled trial showing
controlled trials observing the effects of cinacalcet on coronary artery that a serum phosphate target level of 1.8mmol/l leads to improved
calcification and cardiovascular survival. These studies are: Study to survival versus a serum phosphate of 2.4mmol/l. The recent anaemia
Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification trials – Cardiovascular Reduction Early Anemia Treatment Epoetin Beta
in Subjects With Chronic Kidney Disease Receiving Hemodialysis (CREATE) trial and the Correction of Hemoglobin and Outcomes in Renal
(ADVANCE) and EValuation Of Cinacalcet HCl Therapy to Lower Insufficiency (CHOIR) trial – should warn us against making too definite
CardioVascular Events (EVOLVE). Both studies are currently recruiting assumptions from epidemiology. ■
1. Block GA, Hulbert-Shearon TE, Levin NW, Port FK, Association calcium on coronary artery calcification in patients new to 3-year study, Nephron Clin Pract, 2006;102:c61–71.
of serum phosphorus and calcium x phosphate product with hemodialysis, Kidney Int, 2005;68:1815–24. 19. D’Haese PC, Spasovski GB, Sikole A, et al., A multicenter study
mortality risk in chronic hemodialysis patients: a national study, 11. Chertow GM, Burke SK, Raggi P, Sevelamer attenuates the on the effects of lanthanum carbonate (Fosrenol) and calcium
Am J Kidney Dis, 1998;31:607–17. progression of coronary and aortic calcification in hemodialysis carbonate on renal bone disease in dialysis patients, Kidney Int,
2. Block GA, Klassen PS, Lazarus JM, et al., Mineral metabolism, patients, Kidney Int, 2002;62:245–52. 2003;Suppl:S73–78.
mortality, and morbidity in maintenance hemodialysis, J Am Soc 12. Ferramosca E, Burke S, Chasan-Taber S, et al., Potential 20. Lacour B, Lucas A, Auchere D, et al., Chronic renal failure is
Nephrol, 2004;15:2208–18. antiatherogenic and anti-inflammatory properties of sevelamer associated with increased tissue deposition of lanthanum
3. Young EW, Albert JM, Satayathum S, et al., Predictors and in maintenance hemodialysis patients, Am Heart J, 2005;149: after 28-day oral administration, Kidney Int, 2006;67:
consequences of altered mineral metabolism: the Dialysis 820–25. 1062–9.
Outcomes and Practice Patterns Study, Kidney Int, 2005;67: 13. Brandenburg V, Meert N, Busch B, et al., Influence of sevelamer 21. Slatopolsky E, Liapis H, Finch J, Progressive accumulation of
1179–87. treatment on fetuin-A, CRP and indoxyl sulfate levels – results lanthanum in the liver of normal and uremic rats, Kidney Int,
4. Slinin Y, Foley RN, Collins AJ, Calcium, phosphorus, parathyroid from a prospective crossover study, Nephrol Dial Transplant, 2005;68:2809–13.
hormone, and cardiovascular disease in hemodialysis patients: 2006;21(S4):82 (abstract). 22. Persy VP, Behets GJ, Bervoets AR, et al., Lanthanum: a safe
the USRDS waves 1, 3, and 4 study, J Am Soc Nephrol, 14. Suki W, Zabaneh R, Cangiano J, et al., The DCOR Trial – phosphate binder, Semin Dial, 2006;19:195–9.
2005;16:1788–93. A Prospective, Randomized Trial Assessing the Impact on 23. Block GA, Martin KJ, de Francisco AL, et al., Cinacalcet for
5. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al., Survival Outcomes of Sevelamer in Dialysis Patients, J Am Soc Nephrol, secondary hyperparathyroidism in patients receiving
predictability of time-varying indicators of bone disease in 2005;16:TH-PO745. hemodialysis, N Engl J Med, 2004;350:1516–25.
maintenance hemodialysis patients, Kidney Int, 2006;70: 15. Block GA, Raggi P, Bellasi A, et al., Mortality effect of coronary 24. Colloton M, Shatzen E, Miller G, et al., Cinacalcet HCl
771–80. calcification and phosphate binder choice in incident attenuates parathyroid hyperplasia in a rat model of secondary
6. Stoffels, et al., 2007, personal communication hemodialysis patients, Kidney Int, 2007;71:438–41. hyperparathyroidism, Kidney Int, 2005;67:467–76.
7. Kestenbaum B, Sampson JN, Rudser KD, et al., Serum phosphate 16. Mathew S, Lund RJ, Strebeck F, et al., Reversal of the adynamic 25. Lopez I, Aguilera-Tejero E, Mendoza FJ, et al., Calcimimetic
levels and mortality risk among people with chronic kidney disease, bone disorder and decreased vascular calcification in chronic R-568 decreases extraosseous calcifications in uremic rats
J Am Soc Nephrol, 2005;16:520–28. kidney disease by sevelamer carbonate therapy, J Am Soc treated with calcitriol, J Am Soc Nephrol, 2006;17:795–804.
8. Eknoyan G, Levin A, Levin N, K/DOQI clinical practice guidelines Nephrol, 2007;18:122–30. 26. Takahashi Y, Tanaka A, Nakamura T, et al., Nicotinamide
for bone metabolism and disease in chronic kidney disease, Am 17. Joy MS, Finn WF, Randomized, double-blind, placebo- suppresses hyperphosphatemia in hemodialysis patients, Kidney
J Kidney Dis, 2003;42 (Suppl. 3):S1–S201. controlled, dose-titration, phase III study assessing the efficacy Int, 2004;65:1099–1104.
9. Asmus HG, Braun J, Krause R, et al., Two year comparison of and tolerability of lanthanum carbonate: a new phosphate 27. Charra B, Chazot C, Jean G, et al., Long 3 x 8 hr dialysis: A
sevelamer and calcium carbonate effects on cardiovascular binder for the treatment of hyperphosphatemia, Am J Kidney three-decade summary, J Nephrol, 2003;16 (Suppl. 7):S64–9.
calcification and bone density, Nephrol Dial Transplant, Dis, 2003;42:96–107.
2005;20:1653–61. 18. Hutchison AJ, Maes B, Vanwalleghem J, et al., Long-term
10. Block GA, Spiegel DM, Ehrlich J, et al., Effects of sevelamer and efficacy and tolerability of lanthanum carbonate: results from a
26 EUROPEAN RENAL DISEASE 2007