What are the recommended phosphate lowering agents for patients with chronic kidney disease (CKD) who are not on dialysis?

Phosphate Lowering Agents for CKD Patients Not on Dialysis

In CKD G3a-G5 patients not on dialysis with persistent or progressive hyperphosphatemia, initiate treatment with dietary phosphate restriction (800-1000 mg/day) first, then add phosphate binders if needed, with non-calcium-based binders (sevelamer, lanthanum, or iron-based) preferred over calcium-based binders to minimize vascular calcification risk. 1

When to Initiate Phosphate-Lowering Treatment

Treatment decisions should be based on progressively or persistently elevated serum phosphate levels, not a single measurement. 1 The target is to lower elevated phosphate toward the normal range, specifically maintaining levels between 2.7-4.6 mg/dL (0.87-1.49 mmol/L) in CKD stages 3-4. 1

Monitor serum phosphate every 6-12 months in CKD G3a-G3b, every 3-6 months in CKD G4, and every 1-3 months in CKD G5. 2

First-Line Approach: Dietary Phosphate Restriction

Restrict dietary phosphate intake to 800-1000 mg/day (adjusted for dietary protein needs) as initial therapy, either alone or in combination with phosphate binders. 1

Consider the source of dietary phosphate when making recommendations: 1

• Animal-based phosphate is more bioavailable than plant-based
• Phosphate additives in processed foods are highly absorbable and should be avoided

Monitor serum phosphate monthly after initiating dietary restriction to assess response. 1

When to Add Phosphate Binders

Add phosphate binders when dietary restriction alone fails to control serum phosphate or PTH levels within target ranges. 1 This is a grade 2D recommendation for CKD G3a-G5 and grade 2B for CKD G5D. 1

Choice of Phosphate Binder: A Hierarchical Approach

Preferred: Non-Calcium-Based Binders

For CKD G3a-G5 not on dialysis, prioritize non-calcium-based phosphate binders (sevelamer, lanthanum carbonate, or iron-based binders) as first-line agents to avoid positive calcium balance and reduce vascular calcification risk. 1, 3, 4

Specific non-calcium options include:

• Sevelamer (hydrochloride or carbonate): Does not accumulate systemically, has pleiotropic cardiovascular benefits including improved lipid profiles and reduced inflammation, and may attenuate coronary and aortic calcification. 3, 4, 5 Sevelamer commonly causes constipation (RR 6.92). 5

• Lanthanum carbonate: Higher phosphate-binding efficacy than sevelamer, requiring fewer tablets, and appears to decrease vascular calcification development. 3, 6 However, lanthanum is absorbed and accumulates in bone tissue with uncertain long-term consequences. 3, 4, 7 Lanthanum probably increases constipation (RR 2.98) and may cause vomiting (RR 3.72). 5

• Iron-based binders (ferric citrate, sucroferric oxyhydroxide): Effective phosphate control with the added benefit of treating anemia in CKD patients not on dialysis, avoiding need for separate oral iron supplementation. 6, 5 Iron-based binders probably cause constipation (RR 2.66) and diarrhea (RR 2.81). 5

Conditional Use: Calcium-Based Binders

Calcium-based phosphate binders (calcium acetate or carbonate) may be used as initial therapy with modest doses (<1 gram elemental calcium daily), but restrict total elemental calcium from binders to ≤1,500 mg/day and total calcium intake (including dietary) to ≤2,000 mg/day. 1, 3

Avoid or discontinue calcium-based binders in the following situations: 1

• Presence of arterial or vascular calcification (grade 2C)
• Adynamic bone disease (grade 2C)
• Persistently low serum PTH levels (grade 2C)
• Corrected serum calcium >10.2 mg/dL (2.54 mmol/L) or persistent hypercalcemia
• PTH <150 pg/mL on two consecutive measurements

The concern with calcium-based binders is their association with hypercalcemia, parathyroid gland suppression, adynamic bone disease, and vascular/soft tissue calcification, particularly when doses exceed 1.2-2.3 grams of elemental calcium daily. 3, 4

Agents to Avoid

Avoid long-term use of aluminum-containing phosphate binders due to risk of aluminum intoxication affecting the central nervous system, bone, and hematopoietic cells. 1, 4 Aluminum may only be used short-term (≤4 weeks, one course only) for severe hyperphosphatemia >7.0 mg/dL (2.26 mmol/L), then replaced with other binders. 1

Individualizing Binder Selection

The choice of phosphate binder should account for: 1

• CKD stage (earlier stages may tolerate calcium better)
• Presence of vascular calcification (favor non-calcium binders)
• Serum calcium levels (avoid calcium if elevated or high-normal)
• PTH levels (avoid calcium if PTH is low)
• Concomitant therapies (especially vitamin D analogs)
• Side effect profile and patient tolerability
• Cost considerations (calcium-based binders are least expensive)

Combination Therapy Strategy

When monotherapy with either calcium-based or non-calcium-based binders fails to control hyperphosphatemia, use combination therapy with both types. 1, 3 Start with modest doses of calcium-based binders (<1 gram elemental calcium), then add a non-calcium-based agent when larger doses are required. 3

Integration with PTH Management

When treating elevated PTH in CKD G3a-G5 not on dialysis, address hyperphosphatemia as a modifiable factor by: 1, 2, 8

• Reducing dietary phosphate intake
• Administering phosphate binders
• Adding calcium supplements if hypocalcemic
• Supplementing native vitamin D (ergocalciferol or cholecalciferol) if deficient

Reserve calcitriol and vitamin D analogs for CKD G4-G5 with severe and progressive hyperparathyroidism, not for routine use in earlier CKD stages. 1 This represents a significant change from 2009 guidelines, which recommended more liberal use of active vitamin D. 1

Critical Safety Monitoring

Avoid hypercalcemia in all CKD stages G3a-G5D. 1, 8 If corrected total serum calcium exceeds 10.2 mg/dL (2.54 mmol/L): 1, 8, 9

• Reduce or discontinue calcium-based phosphate binders
• Reduce or stop calcitriol/vitamin D analogs
• Switch to non-calcium-based binders

Monitor for hypercalcemia monthly for the first 3 months after initiating or adjusting phosphate binders or vitamin D therapy, then every 3 months once stable. 2, 9

Common Pitfalls to Avoid

• Do not use calcium-based binders as monotherapy in patients with documented vascular calcification – this may accelerate calcification progression. 1
• Do not exceed 1,500 mg/day of elemental calcium from binders – higher doses increase risk of positive calcium balance and vascular calcification. 1, 3
• Do not ignore gastrointestinal side effects – poor adherence due to constipation (sevelamer, lanthanum, iron) or diarrhea (iron) undermines phosphate control. 5, 7
• Do not routinely use active vitamin D (calcitriol) in CKD G3a-G5 not on dialysis – this increases hypercalcemia risk (22-43% incidence) without clear mortality benefit. 1, 2