Journal Club

Ten-Year Experience with Sevelamer and Calcium Salts as Phosphate Binders. Paolo Raggi, Sobodan Vukicevic, Rosa Maria Moyses, Katherine Wesseling, and David M. Spiegel. Clin J Am Soc Nephrol 5: S31-S40, 2010.

Overview:

Caution: industry-sponsored

Big Question: Is there less vascular calcification, thus a greater survival advantage, with sevelamer versus calcium-based phosphate binders in severe CKD?

Hypotheses:

1. CKD --> abnormal Ca, P, PTH, Vit D metab

--> vascular calcification (VC)

--> increased CV disease / mortality

2. Hyper-P assoc w/ VC / increased mortality

3. Sevelamer slows development of VC whereas Ca salts do not

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Binder effects are discussed in four areas:

Biomarkers, VC, bone homeostasis, mortality

Conclusion

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Biomarkers

Lipids:

['classical' risk factor for cardiovascular disease]

sevelamer --> reduced total cholesterol and LDL [decreased GI absorption], reduced apoliprotein B

Ca salts --> no data offered

CRP:

[acute-phase reactant, often elevated in HD pts; associated with overall and cardiovascular death in HD pts

sevelamer --> reduced CRP

Ca salts --> no change

Fetuin-A:

[Inhibits Ca/P crystal deposition; low levels associated with worse cardiovascular calcification status]

sevelamer --> increased fetuin-A

Ca salts --> no change

Phosphorus, PTH:

[P and PTH levels associated with increased mortality in pts with CKD]

sevelamer == Ca salts

Fibroblast growth factor 23 (FGF-23):

[inhibits tubular reabsorption of phosphate; higher FGF-23 and P levels associated with increased mortality; possible marker of response to phosphate binder therapy]

sevelamer --> change 3x that of Ca salts

sevelamer + Ca salts --> decr. FGF-23

Ca salts --> no change

[50% within-subject variations of biomarkers relative to total variation in measurements in CKD ]

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Vascular Calcification

Pts with advanced CKD have increased risk for VC w/ predicts morbidity/mortality. There is reported association between increased P and greater prevalence of VC in pts with moderate to severe CKD. Thus P-lowering rx may reduce VC and decrease mortality [Rx P-binder --> improved survival , independent of baseline/follow-up P levels].

Stt. sugest risk for VC / arterial stiffness greater w/ Ca-based binder as compared w/ sevelamer.

1. Renagel in New Dialysis (RIND) [prospective randomized; sevelamer / Ca-based --> progression of VC]. Absolute median coronary artery calcification (CAC) score increase 11-fold greater w/ ca-based vs sevelamer. Both arms had signif increased CAC score. [note - Raggi]. Greater baseline CAC score predictor all-cause mortality at 4.5 yr.

2. Treat to Goal (TTG); 200 adult HD, sevelamer vs ca-based 52 wks.Binder, dialysate Ca, vit D titrated to Ca <10.5, P 3.5-5.5, PTH 150-350; 83% had CAC at baseline; median % change CAC score > w/ ca-based vs sevelamer, more freq. suppression PTH w/ ca-based

3. Calcium Acetate Renagel Evaluation 2 (CARE 2); non-inferiority trial, compare Ca acetate vs sevelamer on progression of CAC. 203 HD pts randomly given Ca acetate or sevelamer, P titrated to 2.5-5.5, LDL titrated to <70 w/ atorvastatin; mean increase CAC score 35% ca acetate, 39% sevelamer (NS); sevelamer non-inferior to ca acetate in CAC progression; numerous limitations cited - PTH high in sevelamer pts; high dropout rate ca acetate; most used atorvastatin w/ might increase CAC score; concern over co-morbidity in pt selection.

4. Phosphate Binder Impact on Bone Remodeling and Coronary Calcification (BRiC): 101 HD, randomly assigned ca acetate or sevelamer; no difference bone remodeling or CAC progression. Sevelamer pts required higher Ca dialysate.

5. Russo et al: 90 pre-dialysis pts, binder, vit d, statin naive; Rx low-P diet, ca co3 or sevelamer 2 yr. Annual progression in CAC low-P diet > ca c03 > sevelamer. No mention of significance of results.

Summary: suggest Ca-based binder may accelerate VC. Inconsisent results in clinical studies. Statistical problem: with small clinical trials, null hypothesis will not be rejected in some cases even when true differences exist.

Bone Homeostasis

In adults, no data RE Ca supplement reduces risk of fx or increases bone density. Non-Ca binders =/= ca-based binders regarding bone turnover, mineralization, volume; no info RE fx risk.

Mathew: rx sevelamer reduced cholesterol and P in model of murine metabolic synd. w/ CKD; sevelamer reduced VC

No difference bone turnover [ca- co3 / sevelamer , 1 yr, HD]. Bone formatin rate (BFR) increased w/ sevelamer, no change w/ ca co3 (thus might be advantageous in adynamic bone).

Sevelamer == ca co3 (both w/ vit d) pediatric pts w/ high PTH and osteitis fibrosa regarding P, PTH, BFR.

Ped pts, hi PTH; ca co3 > sevelamer RE mineralization. Intake of Ca below RDA in sevelamer pts.

111 HD pts, decrease vertebral travecular bone density ca-based vs sevelamer --> trend towards decreased BMD despite incr. Ca level

Mortality

RIND: improved mortality sevelamer vs ca-based

VA retro study: HR death 0.67 sevelamer vs ca-based

Dialysis Clinical Outcomes Revisited (DCOR): no diff.

CMS data: no diff

meta-analyses x 2: no difference

No robust statistically significant difference for mortality

Authors Opinion: the evidence so far accumulated is reassuring and provides an important signal as to the advantage of sevelamer over calcium salts for phosphate binding.

Conclusion

KDIGO: restrict/avoid ca-based binder with proven VC, persisent hyper-Ca, and hyperPTH, or adynamic bone

Sevelamer == lower incidence hyperCa, VC w/o low Ca

Differential effects on bone structure / function may result

Suggest better survival sevelamer > ca-based

Pick binder not just to reduce P, but consider overall potental benefits on mineral homeostasis, bone histomorphometry, vasculature biology, mortality

Links:

Ten-Year Experience with Sevelamer and Calcium Salts as Phosphate Binders. Paolo Raggi, Sobodan Vukicevic, Rosa Maria Moyses, Katherine Wesseling, and David M. Spiegel. Clin J Am Soc Nephrol 5: S31-S40, 2010.