Oral Phosphate Binders in Patients with Kidney Failure 김정현 NEJM 2010;362:1312-24

Phosphate Metabolism in Kidney Failure and in Health

Putative Mechanisms Linking Hyperphosphatemia and Cardiovascular Disease

Target ranges of Ca, P & PTH

Phosphate control Restriction of dietary phosphorus : 유제품, 간, 육류, 콩류, 견과류, 정백하지 않은 빵과 곡류, 탄산음료(특히 콜라) Phosphate binders Dialysis

Phosphate-Binding Agents Aluminum Systemic aluminum toxicity : encephalopathy, osteomalacia, anemia Calcium-based phosphate binders Sevelamer Lanthanum Magnesium-based phosphate binders

Calcium-Based Phosphate Binders

Calcium-Based Phosphate Binders Calcium carbonate Calcium acetate K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease

Calcium-Based Phosphate Binders Calcium carbonate Calcium acetate Am J Kidney Dis 2009;54:619-37.

Common Drug Interactions and Adverse Events with Phosphate Binders

Calcium-Based Phosphate Binders Binder source Forms Content Potential advantages Potential disadvantages Calcium acetate Capsule, tablet Contains 25% elemental Ca2+ (169mg elemental Ca2+ per 667mg cap) Effective P-binding, potentially for enhanced P-binding capability over CaCO3 potentially less calcium absorption Potential for hypercalcemia-associated risks including extraskeletal calcification and PTH suppression; more costly than CaCO3; GI side effects carbonate Liquid, tablet, chewable, capsule, gum Contains 40% elemental Ca2+ (200mg elemental Ca2+ per 500mg CaCO3) Effective, inexpensive, readily available Potential for hypercalcemia-associated risks including extraskeletal calcification and PTH suppression; GI side effects citrate Tablet, liquid, capsule Contains 22% elemental Ca2+ Not recommended in CKD Enhancement of aluminum absorption; GI side effects Calcium ketoglutartate Similar to other calcium salts, costly, GI side effects, potentially less hypercalcemic than calcium carbonate or acetate, not well studied gluconate Tablet, powder Similar to other calcium salts, not well studied KDIGO. Chapter 4.1 : Treatment of CKD–MBD targeted at lowering high serum phosphorus and maintaining serum calcium Kidney Int 2009;76:Suppl 113:S50-S99

Sevelamer

Sevelamer (1) Clinical Outcomes

Sevelamer hydrochloride Nonabsorbable agents, a cationic polymer binding phosphate through ion exchange Lower incidence of hypercalcemia (5 vs. 16%) Decreased incidence of low PTH levels (30 vs. 57%) Lower LDL-C (65 vs. 103 mg/dL) Much lower % increases in median absolute Ca- scores in coronary arteries (5 vs. 25%) & aorta (5 vs. 23%) Kidney Int 2002;62:0245-252

Sevelamer vs Calcium-based phosphate binders : Mortality in Hemodialysis patients DCOR study (Dialysis Clinical Outcomes Revisited) Primary objective : To compare all-cause mortality and cause-specific mortality (cardiovascular mortality, infection, and other causes) among hemodialysis patients treated with calcium based phosphate binders and sevelamer. Design : multi-center, randomized, open-label, parallel design trial (n=2,103, treatment period:45mo) Cohort = ARIC(atherosclerosis risk in communities) study + CHS study Kidney Int 72:1130-1137, 2007

Nephrol Dial Transplant 2007;22: 2856–2866 Systematic review of the clinical efficacy and safety of sevelamer in dialysis patients Conclusions. Compared with calcium-based phosphate binders, use of sevelamer in dialysis patients is associated with similar to slightly higher phosphate levels, similar calcium phosphate product, and slightly lower serum calcium levels. There was no evidence that sevelamer reduced all-cause mortality, cardiovascular mortality, the frequency of symptomatic bone disease or health-related quality of life. Nephrol Dial Transplant 2007;22: 2856–2866

Sevelamer vs Calcium-based phosphate binders CARE study (The Calcium Acetate Renagel Evaluation) Primary objective : To compare the efficacy of calcium acetate and sevelamer hydrochloride for Serum phosphorus control in patients with ESRD on HD Desing : randomized double-blind study (n=100, treatment period:8wks) Exclusion criteria : iPTH > 1000 pg/mL, or a history of previous parathyroidectomy P = NS P = 0.0017 Calcium acetate controls serum phosphorus and calcium-phosphate product more effectively than sevelamer hydrochloride. Cost-benefit analysis indicates that in the absence of hypercalcemia, calcium acetate should remain the treatment of choice for hyperphosphatemia in HD patients Kidney Int 2004;65:1914-1926

No randomized trials have compared health- related quality of life, occurrence of cardiovascular events, or presence of symptomatic bone disease between patients receiving sevelamer and those receiving calcium-based preparations or other agents. There is no conclusive evidence that treatment with sevelamer improves clinically relevant end points when it is compared with other currently available phosphate binders.

Sevelamer (2) Vascular Calcification and Histologic Features of Bone

A pooled estimate from a recent meta-analysis that included five of seven available studies suggested that the effect of sevelamer on vascular calcification was not significant. The available studies do not indicate that sevelamer improves the histologic features or turnover of bone, as compared with calcium. Nephrol Dial Transplant 2009;24: 3168–3174 Nephrol Dial Transplant 2005;20: 1653–61 JASN 2008;19: 405–412

Common Drug Interactions and Adverse Events with Phosphate Binders

Lanthanum

(2) Vascular Calcification and Histologic Features of Bone (1) Clinical End points No good-quality studies have been powered to examine the effect of lanthanum on clinical end points. No studies have assessed the effect of lanthanum on vascular calcification. (2) Vascular Calcification and Histologic Features of Bone

(3) Biochemical End points Lanthanum and calcium-based phosphate binders : similarly effective in reducing serum phosphate concentrations in patients with ESRD Clin Nephrol 2006;65:191-202 Clin Nephrol 2005;64:428-37

(4) Safety Withdrawals due to adverse events were more frequent among the lanthanum-treated patients than among those who received other phosphate binders (usually calcium-based). Although lanthanum is poorly absorbed, bone- biopsy specimens from patients who had been treated with lanthanum for up to 4.5 years showed rising levels of lanthanum over time. CEDAC final recommendation on reconsideration and reasons for recommendation: lanthanum carbonate hydrate, 2008.

Common Drug Interactions and Adverse Events with Phosphate Binders

Magnesium-Based Phosphate Binders

Common Drug Interactions and Adverse Events with Phosphate Binders

Use of Phosphate Binders in CKD In CKD Patients (Stages 3 and 4): If phosphorus or intact PTH levels cannot be controlled within the target range, despite dietary P restriction, P binders should be prescribed. Ca-based phosphate binders are effective in lowering serum P levels and may be used as the initial binder therapy. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease

lowering serum P levels and either may be used as the primary therapy. In CKD Patients with Kidney Failure(Stage 5) Both Ca-based P binders and non-Ca, non-Al, and non-Mg containing P-binding agents are in lowering serum P levels and either may be used as the primary therapy. In dialysis patient who remain hyperphosphatemic (serum P>5.5 mg/dL) despite the use of either of Ca-based P binders or other non-Ca, non-Al, and non-Mg containing P-binding agents, a combination of both should be used. K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease

IIn CKD Patients with Kidney Failure(Stage 5) The total dose of elemental calcium provided by the Ca-based P binders should not exceed 1,500 mg/d, and the total intake of elemental Ca (including dietary Ca) should not exceed 2,000 mg/d. Ca-based phosphate binders should not be used in dialysis patients who are hypercalcemic (corrected serum Ca>10.2 mg/dL), or whose plasma PTH<150 pg/mL on 2 consecutive measurements.

In CKD Patients (Stage 5): Non-Ca containing P binders are preferred in dialysis patients with severe vascular and/or other soft-tissue calcifications. In patients with serum P>7.0 mg/dL, Al-based P binders may be used as a short-term therapy(4wks), and for one course only, to be replaced thereafter by other P binders. In such patients, more frequent dialysis should also be considered.