Hyperphosphatemia management in ESKD patients: The "3Ds" - Diet, Dialysis and Drugs

19 Jan 2023

Hyperphosphatemia (i.e., serum phosphate >5.6mg/dL) is associated with a higher risk of mortality in a fully adjusted model.1 In the ASN Kidney Week 2022, Professor Michal L. Melamed from Albert Einstein College of Medicine, the United States (US), presented her group’s study on the hyperphosphatemia management which interventions to lower phosphate include the “3Ds” – diet (i.e., low phosphate diet), dialysis (i.e., frequent weekly dialysis sessions), and drugs (i.e., medications to reduce the phosphate levels).1 

Diet refers to teaching dialysis patients to read food labels. Study has shown that it helped reduce the phosphate levels by a difference of -0.6mg/dL (95% CI: -1.0 to -0.1; p=0.03) comparing the intervention and control groups.1 Similar study was conducted via telehealth due to the Coronavirus disease of 2019 (COVID-19) on 156 dialysis patients, during which a dietician provided nutritional advice to the patient or caregiver, with a result showing a reduction in the phosphate levels from 6.5mg/dL (6.1-7.2) to 5.5mg/dL (4.7-6.1).1 In addition, multiple studies have shown that different types of food have a varying bioavailability of phosphate, such as plants (e.g., grains, legumes nuts) having a bioavailability of 30%-50%, while inorganic additives (e.g., soda, prepared or canned foods) reaching 90%-100%.1 Highly motivated chronic kidney disease (CKD) patients, who were placed on a mostly plant-based diet, saw a decrease in the urine phosphate levels from 830 ± 244mg/24hrs to 615 ± 273mg/24hrs (p=0.001) in 4 weeks.1 

Dialysis is effective in decreasing the phosphate levels; however, frequent and longer periods of dialysis are required to sustain its effectiveness.1 A study comparing 6 times and 3 times a week dialysis has shown that a 6 times a week dialysis is associated with a mean decrease in predialysis phosphate, left ventricle (LV) mass, and predialysis systolic blood pressure.1 

All phosphate binders have unique side effects.1 The most frequently used phosphate binders include sevelamer hydrochloride, lanthanum carbonate, and iron-based binders.1 All of which have gastrointestinal side effects.1 Observational studies on 6,000 patients have shown the relationship between phosphate binder use and improved survival even at a normal baseline phosphate level and in all types of phosphate binders excluding aluminum-based binders.1 Studies comparing lanthanum carbonate and calcium carbonate showed no significant difference in the primary outcome of cardiovascular (CV) events such as CV death, nonfatal myocardial infarction (MI) or stroke, unstable angina (UA), and hospitalization for heart failure (HF) or ventricular arrhythmia (HR=1.11; 95% CI:=0.88-1.41; p=0.37), nor other secondary outcomes such as all-cause death, CV death, secondary hyperparathyroidism (HPT), and hip fracture.

During the COVID-19, a higher phosphate level was associated with increased mortality in the intensive care unit (ICU) patients with acute kidney injury and the COVID-19 pneumonia.1 It was also shown that among patients with severe COVID-19, those who have pre-existing kidney diseases (i.e., dialysis-dependent or CKD) had a higher risk of 28-day in-hospital death, with an absolute death rate of 50% for dialysis-dependent patients [adjusted HR (aHR)=1.41; 95% CI=1.09-1.81] and 51% for CKD patients (aHR=1.25; 95% CI=1.08-1.44).1 This was attributed to the effects of COVID-19 and other natural disasters, which had potentially led to decreased access to dialysis and healthy food.1 

New medications that may lower the phosphate levels but are yet to obtain approval by the US Food and Drug Administration (FDA) include tenapanor, nicotinamide, and EOS789.1 Tenapanor blocks the sodium/hydrogen exchanger isoform 3 (NHE3), while nicotinamide blocks the sodium phosphate co-transporter (NaPi-2b).1 Most promisingly, multiple studies have shown that EOS789, which blocks NaPi-2b, pituitary-specific transcription factor-1 (PiT-1), and PiT-2, was a safe and well tolerated drug.1 

Ongoing clinical trials that assess the hyperphosphatemia treatment include the HiLo study and the Pragmatic Randomised Trial of High or Standard Phosphate Targets in End-Stage Kidney Disease (PHOSPHATE).1 The former aims to compare the mean phosphate levels of 4.8-5.2mg/dL to 6.5-6.8mg/dL in >4,000 patients with end-stage kidney disease (ESKD), while the latter aims to compare the mean phosphate levels of <4.6mg/dL to >6.6mg/dL in 3,600 ESKD patients.1 

To conclude, hyperphosphatemia is related to higher mortality, especially among COVID-19 patients.1 Diet, dialysis, and drugs, the so-called “3Ds”, are essential for hyperphosphatemia control, with various binders of unique safety profiles accessible.1 Patients with ESKD and COVID-19 have an increased risk of hyperphosphatemia, likely due to changes in diet and dialysis schedule.1 While studies assessing the advantages of hyperphosphatemia treatments are in progress, new treatments for hyperphosphatemia are anticipated.1 

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