A Case for Calcium-Based Binders
Joseph A. Coladonato, MD
Hyperphosphatemia is a common complication among patients with end-stage renal disease (ESRD) and is associated with many adverse clinical consequences, including an increased mortality risk (Am J Kidney Dis. 1998;31:607-617).
Specifically, there has been a reported association between hyperphosphatemia (phosphorus level higher than 5.0 mg/dL) and increased risk of cardiovascular mortality (J Am Soc Nephrol. 2004;15:2208-2218). Therefore, control of phosphorus is essential in the clinical management of ESRD patients to reduce the risk of these adverse outcomes. The best choice of phosphate binder to achieve these goals is controversial.
Concerns of calcium loading and cardiovascular calcification (CVC) recently have become a potent driving force for selecting phosphate binders (Nephrol Dial Transplant. 2002;17:229-232). These concerns became widespread with publication of the Treat to Goal (TTG) study, which compared sevelamer (a noncalcium, nonaluminum polymer) with calcium salts (carbonate and acetate) (Kidney Int. 2002;62:245-252).
TTG was the first large, prospective, randomized trial to study the effects of different phosphate binders on CVC as measured by electron-beam computed tomography (EBCT). In the trial, 200 chronic hemodialysis (HD) patients received either sevelamer or a calcium salt. Both classes of agents were equally effective in reducing and maintaining Ca × PO4 product and serum phosphorus levels throughout the study.
Patients randomized to the sevelamer group, however, exhibited an attenuation of coronary and aortic calcification measured by EBCT. Sevelamer recipients also had a significant reduction in total and LDL cholesterol. The investigators hypothesized that these findings were due to calcium loading; unfortunately, the complexity of the study and of clinical practice make it impossible to test this hypothesis fully.
In the sevelamer group, serum calcium levels and the incidence of hypercalcemia were lower compared with patients receiving calcium-based binders. The study design, however, did not establish a clear difference in calcium load between the two groups because alterations in dialysate calcium levels and nocturnal calcium supplementation were allowed at clinicians' discretion.
This is important because calcium absorption varies with different agents and timing of administration. Patients receiving calcium carbonate on an empty stomach had a higher absolute percent of calcium absorbed (468 mg) than patients who received it with meals or who received calcium acetate instead (299 mg) (J Clin Invest. 1989;83:66-73).Another confounding factor was the failure to control LDL and total cholesterol in all study patients. Calcium ingestion may play a role, but ESRD patients have numerous cardiovascular risk factors, so it is important to design a study that controls for these risk factors in addition to the type of phosphate binder used.
The Calcium Acetate Renagel Evaluation-2 (CARE-2) study was designed to address the study limitations of TTG (Am J Kidney Dis. 2008;51:952-965). Investigators randomized 203 chronic HD patients to either sevelamer or calcium acetate. Atorvastatin was given to the entire calcium group and to some of the sevelamer group to achieve LDL levels below 70 mg/dL. Dialysate calcium was fixed at 2.5 mEq/L, and no nocturnal supplementation of calcium was allowed in the sevelamer group. Vitamin D therapy was flexible, but guidelines were provided to clinicians.
The geometric mean increases in EBCT calcium scores were similar between the two groups. These results support the noninferiority hypothesis: There was no significant difference in CVC progression following equivalent lipid control in the calcium acetate- and sevelamer-treated groups. The data suggest that lipid lowering may play an important role in attenuating CVC progression and that the beneficial effect observed in TTG may be related to sevelamer's LDL-lowering effect.
Moreover, the daily calcium absorbed from use of calcium acetate as a phosphate binder for one year does not appear to contribute to progression of CVC in HD patients, and intensive LDL lowering does not halt progression or induce regression of CVC. Therefore, factors other than LDL levels may play a key role in CVC progression in ESRD patients.