Effects of phosphate binders in moderate CKD.
+10 authors
Journal: 2012/October - Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Abstract:
Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.
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J Am Soc Nephrol 23(8): 1407-1415
PMID: 22822075

Effects of Phosphate Binders in Moderate CKD

+6 authors
Denver Nephrology, Denver, Colorado;
Centre for Nephrology, Royal Free Campus, University College London Medical School, London, United Kingdom;
University of Washington, Seattle, Washington;
Nephrologische Klinik, Klinikum Coburg, Coburg, Germany;
University of Colorado, Denver, Colorado;
University of California, San Diego, California;
Litholink Corp, Chicago, Illinois;
Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts;
University of Miami, Miami, Florida; and
Stanford University School of Medicine, Palo Alto, California
Corresponding author.
Correspondence: Dr. Geoffrey A. Block, Denver Nephrology, 130 Rampart Way, Suite 300b, Denver, CO 80230. Email: ten.hpenrevned@kcolbag
Received 2012 Mar 2; Accepted 2012 May 10.
Copyright © 2012 by the American Society of Nephrology

Abstract

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20–45 ml/min per 1.73 m to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

Abstract

CKD is a significant public health concern; roughly 13% of the US population has an estimated GFR (eGFR) below 60 ml/min per 1.73 m or albuminuria.1 The risks of death and cardiovascular disease in CKD are not fully explained by associated diabetes, hypertension, and other conventional risk factors.2 With declining kidney function, serum phosphorus concentration increases but generally remains within the normal range until late in stage 4 or 5 CKD. A normal or near-normal serum phosphorus concentration is maintained at the expense of elevated levels of the phosphaturic hormones parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23).34 Serum concentrations of phosphorus and hormones responsible for its regulation have been implicated as putative cardiovascular risk factors.59

Three intestinal phosphate binders are approved for the treatment of hyperphosphatemia in patients with ESRD in the United States—calcium acetate (Phoslo; Fresenius), lanthanum carbonate (Fosrenol; Shire), and sevelamer carbonate (Renvela; Genzyme)—but none are approved for use in patients with CKD not on dialysis.10 Because higher serum phosphorus concentrations—even within the population reference range—are associated with mortality, some have proposed the use of phosphate binders to lower serum phosphorus in this population.11 We undertook this pilot clinical trial to determine the safety and efficacy of phosphate binders in patients with moderate CKD and normal or near-normal serum phosphorus concentrations.

CAD, coronary artery disease; CHF, congestive heart failure; CVA, cerebro-vascular disease; HTN, hypertension; MI, myocardial infarction; PVD, peripheral vascular disease.

Fisher exact test for all active versus all placebo. GERD, gastro-esophageal reflux disease.

Acknowledgments

The authors would like to acknowledge Stephanie Brillhart, MSCI, and Linda Loftin, NP, for their assistance in the conduct of the trial as the designated unblinded study representatives for study drug storage and assignment. The authors would also like to acknowledge the important contribution of our Data Safety and Monitoring Committee, led by the Chairman, Colin Baigent, FRCP. Members of this committee donated their time and expertise in providing oversight of the trial conduct. In addition to Dr. Baigent, committee members included Grahame Elder, Alistair Hutchison, FRCP, Jonathan Emberson, PhD, and Edmung Ng.

G.A.B., D.C.W., M.S.P., B.K., M.K., D.M.S., J.A., R.T., M.W., and G.M.C. participated in the design, analysis, interpretation, and manuscript preparation. G.S., M.A.A., A.N.H., and M.M. participated in data acquisition, analysis, interpretation, and manuscript preparation. L.K. participated in the design and data acquisition. G.A.B. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding for this investigator-initiated study was provided by Shire, Inc., Fresenius NA, Genzyme, Inc., Denver Nephrologists, PC, Novartis, Inc., and Davita, Inc.

Funding entities had no role in the design, conduct, analysis, interpretation, or preparation of the manuscript. Each funding entity was permitted to review the manuscript for verification that no proprietary or confidential information was included.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

See related editorial, “Phosphate Binders in CKD: Bad News or Good News?,” on pages 1277–1280.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2012030223/-/DCSupplemental.

Footnotes

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