Nephrology Hypertension

Medical Management of the Dialysis Patient: Hyperphosphatemia

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?

Lab Testing

  • 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

Imaging

  • If dialysis adequacy is suboptimal, then imaging studies to assess vascular access patency may be needed

Biopsy

  • 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?

Dietary restriction

  • Usual American diet contains ~800 to 2000 mg of phosphorus/day

  • Major sources of dietary phosphorus are

    • Meat

    • Fish

    • Dairy

    • Grains

    • Vegetables

    • Soft drinks

  • 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

Phosphate binders

  • 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

    1. Average dialysis patient is on numerous medications

    2. Compliance with three times a day drugs is lower than with once daily medications

    3. Pill burden with certain classes of phosphorus binders is large

    4. 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

    1. 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

    2. Calcium-based phosphate binders

      1. Calcium carbonate

      2. Calcium acetate

    • 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

    1. Non-calcium based phosphate binders

    • Sevelamer hydrochloride

      • ▪ Metabolic acidosis

      • ▪ Large pill burden

      • ▪ Cost

    • Severlamer carbonate

      • ▪ Developed to address concern of metabolic acidosis with sevelamer hydrochloride

    • Lanthanum carbonate

      • ▪ 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)

      • ▪ Cost

    • 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

Table I.

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
Peritoneal continuous  
    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

Pharmacologic considerations

  • 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?

Specialty consultations

  • If dialysis adequacy is in question, interventional radiologists may need to be consulted to assess patency and perform vascular access procedures as needed

Nurses

  • enforce medication education, adherence and compliance

Dieticians

  • 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?

Guidelines

Kidney Disease Outcomes Quality Initiative

  • Target range for serum phosphate in CKD stage 5: 3.5-5.5 mg/dl

Table II. KDOQI Guidelines Recommendations for Hyperphosphatemia Treatment

Table II.

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

  1. Develop hypercalcemia

  2. Have evidence of arterial calcification

  3. Have evidence of adynamic bone disease or persistently low PTH levels

Limitations

  • 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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