NDT Advance Access originally published online on May 25, 2007
Nephrology Dialysis Transplantation 2007 22(9):2724-2725; doi:10.1093/ndt/gfm312
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Calcimimetic increases osteoprotegerin and decreases fetuin-A levels in dialysis patients
Email: pmessa{at}policlinico.mi.itSir,
The calcimimetic drug cinacalcet, recently introduced as therapy for Secondary Hyper-Parathyrodism (SHP) in dialysis patients, has greatly enhanced the ability to achieve simultaneous control of parathyroid hormone (PTH), calcium and phosphate [1].
However, there have been no data to show that a better control of mineral metabolic parameters is matched with improved clinical outcomes of vascular calcification processes, and hence, of vascular morbidity and mortality.
Recent studies have shown that both osteoprotegerin (OPG) and Fetuin-A are associated with the vascular calcification process in uraemic patients [2,3].
Of 164 patients from our dialysis centre, we submitted 29 of these having serum i-PTH >300 pg/ml while on standard therapy (calcitriol + phosphate binders) to cinacalcet treatment over a 6-month period.
After an observation period of 3 weeks that included the standard therapy, cinacalcet was started at an initial dose of 30 mg per day. Thereafter, cinacalcet, vitamin D metabolites and phosphate binder doses were adjusted according to i-PTH, c-Ca and Pi levels. Cinacalcet was allowed to be increased by 30 mg steps every 15 days to a maximal allowed dose of 180 mg per day. The drug was reduced or withdrawn if i-PTH levels were <150 pg/ml, if c-Ca was <8.4 mg/dl, or if any adverse events appeared.
Blood levels of i-PTH, c-Ca, inorganic phosphate (Pi), albumin, IL-6, Fetuin-A, OPG were assessed at baseline and at the end of the study period. Intact PTH, c-Ca and Pi levels were also checked every 15 days. Over the 6-month study period, the doses of cinacalcet, vitamin D metabolites, phosphate binders, erythropoietin (EPO), anti-hypertensive (antiHT) drugs and any major and minor adverse events were recorded.
OPG and Fetuin-A were assessed by ELISA (Normal values: OPG 4.1 ± 0.33 pmol/l; Fetuin-A 0.35–0.95 g/l).
IL-6 was determined with a solid-phase, enzyme-labelled, chemiluminescent sequential immunometric assay (Normal values were 0–5.9 pg/ml).
Five of the original 29 patients did not complete the study (two due to cardio-vascular deaths; one for withdrawal after a non-fatal cardio-vascular event; two for receiving renal transplantation), resulting in 24 patients included in the final analysis (16 males; aged 38–78).
Table 1 shows the effects of cinacalcet treatment on i-PTH, c-Ca, Pi and the c-Ca x Pi product. All of these parameters were significantly decreased after cinacalcet therapy.
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The mean dose of cinacalcet utilized at the end of the study was 63.12 ± 40.3 mg per day. There were no significant changes in Vitamin D, Sevelamer, Ca based Pi binder, antiHT drugs or EPO doses.
Following cinacalcet treatment, mean serum OPG levels were significantly increased and serum Fetuin-A levels were significantly decreased (Table 2). On the other hand, there were no significant changes in mean IL-6 values. OPG increments were significantly correlated with the degree of c-Ca reduction (r = 0.445; P = 0.029), whereas Fetuin-A reductions were correlated with reductions in i-PTH levels (r = 0.495; P = 0.024). There were no relationships between IL-6 changes and the main mineral metabolism related parameters.
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Our results agree with previous experimental findings [4] and point to the efficacy of calcimimetic drugs for the control of uraemic SHP.
It was unexpected that 6 months of cinacalcet treatment resulted in highly significant increases in OPG and decreases in Fetuin-A serum levels.
OPG, a cytokine produced and secreted mainly by osteoblasts, has been claimed to play an as yet undefined role in the vascular calcification process. Although a protective effect of increased OPG levels on vascular calcification has been suggested, higher OPG serum levels have been linked to an increased extent of arterial wall calcification, increased mortality rates in uraemic patients, and most importantly, with increased mortality in dialysis patients [3,5]. The clinical significance of the OPG increase observed in our patients and its potential effects on the vascular calcification process cannot be drawn from our data. Interestingly, OPG increases were significantly correlated with the degree of reduction in c-Ca levels. In association with the OPG increases, cinacalcet treatment also caused significant decreases in Fetuin-A levels without changes in IL-6, indicating no change in the inflammatory state in our patients. The Fetuin-A reduction was significantly related to PTH decreases. Previous studies have emphasized an association between low Fetuin-A levels with both increased vascular calcification and cardiovascular mortality [2,6]. From our data, we cannot determine whether the Fetuin-A decrease represents a real increase in risk for the calcification process, or whether it is the consequence of a reduced demand for a feedback defence mechanism, which may be secondary to improved mineral metabolism, by cinacalcet, that reduces the pro-calcification burden. This possibility was proposed in non-dialysed diabetic nephropathy patients [7].
Although we are aware of the main limitation of this preliminary study, the highly significant changes in both OPG and Fetuin-A levels observed in our patients provide a stimulus and starting point for further research in this field.
1Nephrology, Dialysis and
Transplant Unit, Department of
Medicine and
2Clinical Pathology Laboratory
Ospedale Maggiore-Policlinico-
MaRe-IRCCS,
Fondazione, Milano, Italy
Acknowledgements
This study was supported by the grant: ‘Project Glomerulonephritis’ in memory of Pippo Neglia.
Conflict of interest statement. Dr Piergiorgio Messa received lecture fees from AMGEN, ABBOTT, and DOMPE’ BIOTEC. The other authors have no conflict of interest to declare.
References
- Moe SM, Chertow GM, Coburn JW. Achieving NKF-K/DOQITM bone metabolism and treatment goals with cinacalcet HCl. Kidney Int (2005) 67:760–771.[CrossRef][Web of Science][Medline]
- Ketteler M. Fetuin-A and extraosseous calcification in uremia. Curr Opin Nephrol Hypertens (2005) 14:337–342.[Web of Science][Medline]
- Kiechl S, Schett G, Wenning G, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation (2004) 109:2175–2180.
[Abstract/Free Full Text] - Pritzker LB, Scatena M, Giachelli CM. The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival. Mol Biol Cell (2004) 15:2834–2841.
[Abstract/Free Full Text] - Morena M, Terrier N, Jaussent I, et al. Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol (2006) 17:262–270.
[Abstract/Free Full Text] - Stenvinkel P, Wang K, Qureshi AR, et al. Low Fetuin-A levels are associated with cardiovascular death: impact of variations in the gene encoding fetuin. Kidney Int (2005) 67:2383–2392.[CrossRef][Web of Science][Medline]
- Mehrotra R, Westenfeld R, Christenson P, et al. Serum Fetuin-A in non-dialysed patients with diabetic nephropathy: relationship with coronary artery calcification. Kidney Int (2005) 67:1070–1077.[CrossRef][Web of Science][Medline]
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