Medical Management of the Dialysis Patient: Hyperphosphatemia
- Does this patient have hyperphosphatemia?
- What tests to perform?
- How should patients with hyperphosphatemia be managed?
- What happens to patients with hyperphosphatemia?
- How to utilize team care?
- Are there clinical practice guidelines to inform decision making?
Does this patient have hyperphosphatemia?
Signs and symptoms
Typically detected by routine laboratory tests
Symptoms may include pruritus, bone or joint pain
Signs may include radiographic evidence of vascular calcification, eye deposition leading to red eye or conjunctivitis, and calciphylaxis
Values may vary depending on time of day (circadian variation), prandial status, relationship to timing of dialysis, hemolysis of specimen, type of blood sample (serum vs. plasma)
Controversies re appropriate level exist, with Kidney Disease Outcomes Quality Initiative recommending a range of 3-5 mg/dl and Kidney Disease: Improving Global Outcomes recommending levels to be maintained in the normal range
What tests to perform?
Should include serum phosphate, calcium, PTH, and indicators of dialysis adequacy (Kt/V or URR)
Elevated phosphate levels may be accompanied by hypocalcemia and secondary hyperparathyroidism and are indicators of severity of global mineral metabolism abnormalities
Serum phosphate levels are typically checked routinely in outpatient dialysis units on at least monthly basis
If treatments are actively being titrated up or down, then more frequent serum phosphate checks may be needed
If dialysis adequacy is suboptimal, it may worsen hyperphosphatemia and thus adequacy should be monitored and maximized
Medications, compliance with prescriptions, time of intake of binders in relation to meals, and diet should be reviewed along with lab work
If dialysis adequacy is suboptimal, then imaging studies to assess vascular access patency may be needed
If painful non-healing ulcers are discovered and the diagnosis of calciphylaxis is being entertained, a skin biopsy may provide the definitive diagnosis, especially when other skin lesions are also in the differential diagnosis (e.g. Coumadin-induced skin necrosis)
Overall Interpretation of test results
Trends in serum phosphate values are more useful than single measurements
Controversies in diagnostic testing
Kidney Disease Outcomes Quality Initiative recommends checking serum phosphate levels on monthly basis
Kidney Disease: Improving Global Outcomes recommends checking serum phosphate levels 1-3 months
How should patients with hyperphosphatemia be managed?
Usual American diet contains ~800 to 2000 mg of phosphorus/day
Major sources of dietary phosphorus are
Dietary counseling is a crucial component of management
Specific attention needs to be paid to detailed evaluation of components of dietary phosphorus intake:
animal vs vegetable protein
processed food with additives rich in highly bioavailable phosphorus
Counseling for dietary phosphorus restriction must be balanced with risk for protein malnutrition
Counseling to avoid foods with additives may decrease serum phosphate levels
Vegetarian protein contains phosphorus that is less bioavailable than animal protein and may be the preferred source of protein
Because dietary restriction is limited by dietary protein needs, diminishing residual renal function and urinary phosphate excretion, and limited dialytic phosphate removal, additional means of preventing phosphate accumulation are needed
Phosphate binders fill this gap; use increases with increased dialysis vintage
Poor compliance with binder therapy may be a barrier to control
Poor compliance with phosphate binders may be multi-factorial
Average dialysis patient is on numerous medications
Compliance with three times a day drugs is lower than with once daily medications
Pill burden with certain classes of phosphorus binders is large
Gastrointestinal side effects/lack of palatability may limit compliance
Education about proper intake of medications in relation to food is important
Education about importance of therapy may improve compliance
Largest dose of binder should coincide with largest meal of the day
Administered three times a day with meals
Several classes exist
Aluminum-based phosphate binders
▪ Trap phosphate ions in the blood and form unabsorbable aluminum phosphate precipitates in the gut
▪ Useful for short-term therapy
▪ Toxicities (cognitive, bone, heme) prevent long-term use
Calcium-based phosphate binders
Both are effective, inexpensive but use has been curtailed by some due to concerns re hypercalcemia (especially when used in conjunction with active vitamin D) and contribution to vascular calcification (although still controversial and data on hard clinical outcomes lacking)
Recent meta-analyses suggest that calcium carbonate and calcium acetate have similar efficacy in lowering phosphate levels and similar tolerability
Non-calcium based phosphate binders
▪ Metabolic acidosis
▪ Large pill burden
▪ Developed to address concern of metabolic acidosis with sevelamer hydrochloride
▪ Potent, less pills needed to accomplish control of serum phosphate
▪ Long-term data on safety available for 9 years of follow-up
▪ Gastrointestinal (GI) side effects limiting (tolerability may be improved when starting a lowest dose and slowly titrating up)
Magnesium-based phosphate binders
Iron-based phosphate binders: Effectively lowers phosphate; Beneficial effects on iron stores and anemia management
Intensity/adequacy of dialysis (
) Table I
Serum phosphate rapidly cleared within first 2 hours of hemodialysis
Levels rebound 3-4 hours post-treatment
Total amount removed by one hemodialysis treatment on average are 500-1000 mg
Adjustment of other medications
Active vitamin D
▪ Increases dietary phosphorus absorption --> binder dose may need to be titrated up
▪ Increases calcium absorption --> risk of hypercalcemia with calcium-based phosphate binders may increase
Effectiveness of Dialysis Treatment Modalities on Phosphate Removal
|Dialysis Modality||Schedule||Phosphate Removal|
|600 to 1200 mg/session|
|Conventional hemodialysis||4-5h, tiw|
|1800 to 3600 mg/week|
|300 to 360 mg/day|
|2100 to 2520 mg/week|
|600 to 1200 mg/session|
|Nocturnal||6-10h, 5-7 nights/week|
|3000 to 8400 mg/week|
|Short daily dialysis||1.5 to 3h, 5 to 7 days/week||variable|
Controversies in patient management
Given concerns for increased risk for vascular calcification with calcium-based binders some have suggested that calcium-based binders should be used sparingly, if at all
The opposing view is that there is insufficient evidence to support the claim that calcium-based binders are harmful. Proponents of this view also cite increased cost associated with non-calcium based binders and thus advocate use of less expensive calcium-based binders.
What happens to patients with hyperphosphatemia?
Natural history and epidemiology and anatomic and/or pathologic consequences
Several epidemiologic studies support increased mortality in those with elevated phosphate levels
Pharmacoepidemiologic studies suggest that use of binders may be protective on dialysis
Physiologic and/or pathophysiologic implications of hyperphosphatemia
Inhibition of 1,25 Vitamin D
Stimulation of FGF23 production
Contribution to the pathogenesis of secondary hyperparathyroidism
Role in vascular calcification development and progression and direct toxicity to other end-organs, including heart and bone
Binders need to be taken with meals, with largest dose with biggest meal of day
Dose adjustments and switching to/or adding a different class may be necessary once treated with vitamin D
Pill burden is often an issue
GI side effects are also often limiting
How to utilize team care?
If dialysis adequacy is in question, interventional radiologists may need to be consulted to assess patency and perform vascular access procedures as needed
enforce medication education, adherence and compliance
Perform dietary assessments and counseling
Educate patients about hidden sources of phosphorus in form of phosphorus-based additives
Multi-disciplinary care teams may be better able to meet target ranges for management
Are there clinical practice guidelines to inform decision making?
Kidney Disease Outcomes Quality Initiative
Target range for serum phosphate in CKD stage 5: 3.5-5.5 mg/dl
KDOQI Guidelines Recommendations for Hyperphosphatemia Treatment
|< 3.5||assess diet, decrease dose or stop binder|
|>5.5||modify diet, review dialysis freq; adjust binder dose, add another class of binder|
|>7||short term Al-based binder; review diet; increase dialysis|
Dietary phosphorus intake restricted to 800 to 1000 mg/day for those with phosphate >5.5 mg/dl
Total calcium intake from binders should not exceed 1500 mg/day and total intake of calcium, including dietary sources, not to exceed 2000 mg/day
Avoid calcium-based binders in those with hypercalcemia and PTH levels <150 pg/ml and non-calcium based binders preferred in those with vascular and soft-tissue calcification
Kidney Disease: Improving Global Outcomes
Target range for serum phosphate in CKD stage 5: suggestion is lower elevated levels into the normal rang
Restricted use of calcium-based phosphate binders in those who
Have evidence of arterial calcification
Have evidence of adynamic bone disease or persistently low PTH levels
Suggested KDOQI range for phosphate (and other mineral metabolites) is difficult to maintain in practice
While an observation study suggested that individuals who are within KDOQI targets have a better survival experience than those who are not, there are insufficient patient-level data to support the target ranges. Both sets of recommendations are limited by insufficient data on hard clinical outcomes.
Dietary recommendations do not take into account hidden sources of phosphorus, or bioavailability of phosphorus in different foods, types of foods (vegetarian vs. not).
What is the evidence?
Bazari, H, Jaff, MR, Mannstadt, M, Yan, S. "Case records of the Massachusetts General Hospital. Case 7-2007. A 59-year-old woman with diabetic renal disease and nonhealing skin ulcers". N Engl J Med. vol. 20;356. 2007. pp. 1049-1057.(Case presentation of calciphylaxis.)
Block, GA, Hulbert-Shearon, TE, Levin, NW, Port, FK. "Association of serum phosphorus and calcium x phosphate product with mortality in chronic hemodialysis patients: a national study". Am J Kidney Dis. vol. 31. 1998. pp. 607-617.(This is one of the earliest articles that reported an association between abnormalities in mineral metabolism and mortality in dialysis.)
Cannata-Andía, JB, Fernández-Martín, JL, Locatelli, F, London, G, Gorriz, JL, Floege, J, Ketteler, M, Ferreira, A, Covic, A, Rutkowski, B, Memmos, D, Bos, WJ, Teplan, V, Nagy, J, Tielemans, C, Verbeelen, D, Goldsmith, D, Kramar, R, Martin, PY, Wüthrich, RP, Pavlovic, D, Benedik, M, Sánchez, JE, Martínez-Camblor, P, Naves-Díaz, M, Carrero, JJ, Zoccali, C. "Use of phosphate-binding agents is associated with a lower risk of mortality". Kidney Int. vol. 84. 2013. pp. 998-1008.(This observational study reports an independent association between phosphate binder use and lower risk of mortality in the European dialysis population.)
Komaba, H, Kakuta, T, Suzuki, H, Hida, M, Suga, T, Fukagawa, M. "Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia". Nephrol Dial Transplant. vol. 30. 2015. pp. 107-14.(This observational study reports on the association of lanthanum carbonate use in Japanes patients on dialysis and its association with survival.)
Hutchison, AJ. "Oral phosphate binders". Kidney Int. vol. 75. 2009. pp. 906-914.(Comprehensive review of phosphate binders.)
Isakova, T, Gutierrez, OM, Chang, Y, Shah, A, Tamez, H, Smith, K, Thadhani, R, Wolf, M. "Phosphorus binders and survival on hemodialysis". J Am Soc Nephrol. vol. 20. 2009. pp. 388-396.(This is an observational study that reported a survival benefit associated with phosphate binder user in the ESRD setting.)
Kooienga, L. "Phosphorus balance with daily dialysis". Semin Dialysis. vol. 20. 2007. pp. 343-345.(This review article discusses potential effects of daily dialysis on phosphate balance.)
Lewis, J, Dwyer, JP, Koury, M, Sika, M, Schulman, G, Smith, MT, Whittier, FC, Linfert, DR, Galphin, CM, Chuang, P. "Ferric citrate binds phosphorus, delivers iron, and reduces IV iron and erythropoietic stimulating agent use in end-stage renal disease [abstract]". J Am Soc Nephrol. vol. 24. 2013.(This is a study of dialysis patients that demonstrates the potency of iron-based phosphate binders and their salutary effects on anemia management in this population.)
Moe, SM, Zidehsarai, MP, Chambers, MA, Jackman, LA, Radcliffe, JS, Trevino, LL, Donahue, SE, Asplin, JR. "Vegetarian compared with meat dietary protein source and phosphorus homeostasis in chronic kidney disease". Clin J Am Soc Nephrol. vol. 6. 2011. pp. 257-64.(This is a study of patients with CKD that demonstrated beneficial effects of vegetarian diets on mineral metabolism parameters in CKD.)
Slinin, Y, Guo, H, Gilbertson, DT, Mau, LW, Ensrud, K, Rector, T, Collins, AJ, Ishani, A. "Meeting KDOQI guideline goals at hemodialysis initiation and survival during the first year". Clin J Am Soc Nephrol. vol. 5. 2010. pp. 1574-81.(Study that documents difficulties with meeting KDOQI guidelines and the potential for survival advantage with achievement of the targets.)
Sullivan, C, Sayre, SS, Leon, JB, Machekano, R, Love, TE, Porter, D, Marbury, M, Sehgal, AR. JAMA. vol. 11:301. 2009. pp. 629-635.(Randomized controlled trial in patients undergoing dialysis that showed that avoidance of foods enriched with phosphate additives could result in significant lowering of serum phosphate.)
Tonelli, M, Pannu, N, Manns, B. "Oral phosphate binders in patients with kidney failure". N Engl J Med. vol. 362. 2010. pp. 1312-1324.(Comprehensive review of phosphate binders.)
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