1. Oral Phosphate Binders in Patients with Kidney Failure
김정현
NEJM 2010;362:

2. Phosphate Metabolism in Kidney Failure and in Health

3. Putative Mechanisms Linking Hyperphosphatemia and Cardiovascular Disease

4. Target ranges of Ca, P & PTH

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

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

7. Calcium-Based Phosphate Binders

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

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

10. Common Drug Interactions and Adverse Events with Phosphate Binders

11. 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

12. Sevelamer

13. Sevelamer (1) Clinical Outcomes

14. 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:

15. 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: , 2007

16. 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

17. 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 =
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:

18. 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.

19. Sevelamer (2) Vascular Calcification and Histologic Features of Bone

20. 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

21. Common Drug Interactions and Adverse Events with Phosphate Binders

22. Lanthanum

23. (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

24. (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: Clin Nephrol 2005;64:428-37

25. (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.

26. Common Drug Interactions and Adverse Events with Phosphate Binders

27. Magnesium-Based Phosphate Binders

28. Common Drug Interactions and Adverse Events with Phosphate Binders

30. 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

31. 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

32. 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.

33. 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.