What are the causes of hypophosphatemia in patients with end-stage renal disease (ESRD) undergoing dialysis?

Causes of Hypophosphatemia in Dialysis Patients

The primary cause of hypophosphatemia in dialysis patients is excessive phosphate removal during dialysis itself, particularly with intensive (long or frequent) hemodialysis regimens, which can reduce serum phosphate by 0.36-0.5 mmol/L despite increased dietary intake. 1

Dialysis-Related Mechanisms

Intensive Dialysis Regimens

• Long-frequent hemodialysis (increased duration and frequency) causes the most significant phosphate depletion, with phosphate removal directly related to both hours and frequency of dialysis 1
• Kidney replacement therapy (KRT) causes hypophosphatemia in up to 80% of patients during prolonged modalities when standard phosphate-free dialysis solutions are used 2, 3
• Continuous renal replacement therapy leads to hypophosphatemia in 60-80% of ICU patients with acute kidney injury, particularly with prolonged and intensive treatment 2, 4
• The mechanism involves continuous removal of phosphate from the extracellular compartment during dialysis, with limited time for intracellular phosphate to equilibrate 5

Standard Hemodialysis Patterns

• Even conventional hemodialysis causes sharp declines in serum phosphate by the end of treatment, removing phosphate only from the extracellular compartment while phosphate remains predominantly intracellular 5
• Patients with normal predialysis phosphate levels can develop critical postdialysis hypophosphatemia 5

Medication-Related Causes

Phosphate Binder Overuse

• Excessive or continued use of phosphate binders (calcium carbonate, lanthanum carbonate) in patients who have achieved phosphate control can drive levels too low 6, 7
• Up to 40% of patients on long hemodialysis still require phosphate binders, but inappropriate continuation after phosphate normalization causes hypophosphatemia 1

Other Medications

• Diuretics precipitate hypophosphatemia through increased renal phosphate losses in patients with residual kidney function 2, 3
• Intravenous iron formulations (particularly ferric carboxymaltose) cause hypophosphatemia in 47-75% of patients through FGF23 elevation, with severe cases lasting up to 6 months 3

Nutritional and Metabolic Factors

Dietary Restriction

• Overly aggressive dietary phosphate restriction (<800 mg/day) combined with dialysis removal creates negative phosphate balance 1
• The paradox: while dialysis patients typically require phosphate restriction to prevent hyperphosphatemia, those on intensive dialysis often need increased dietary phosphate intake 1

Refeeding Syndrome

• Refeeding or nutritional support initiation triggers intracellular phosphate shifts, particularly problematic in malnourished dialysis patients 2, 3

Patient-Specific Risk Factors

Age and Comorbidities

• Older dialysis patients are significantly more likely to develop hypophosphatemia 7
• Patients with shorter hemodialysis duration (newer to dialysis) show higher risk 7

Gastrointestinal Losses

• Diarrhea contributes to hypophosphatemia through intestinal phosphate losses 2
• Decreased intestinal absorption from any cause compounds dialysis-related losses 8

Hormonal Dysregulation

Hyperparathyroidism

• Both primary and secondary hyperparathyroidism cause ongoing phosphaturia through PTH-mediated renal phosphate loss in patients with residual kidney function 3, 8

FGF23-Mediated Disorders

• Elevated FGF23 (from medications like IV iron or underlying disorders) causes renal phosphate wasting even in dialysis patients with residual function 3

Vitamin D Deficiency

• Vitamin D deficiency leads to secondary hyperparathyroidism and subsequent renal phosphate loss 3

Critical Clinical Pitfalls to Avoid

• Do not ignore persistent hypophosphatemia unresponsive to supplements, as this suggests underlying causes beyond dialysis removal 3
• Monitor phosphate closely during continuous renal replacement therapy—proactive supplementation with phosphate-containing dialysis solutions prevents the 60-80% incidence of hypophosphatemia 3
• Recognize that normal predialysis phosphate does not exclude postdialysis hypophosphatemia, particularly in patients on intensive dialysis regimens 5
• Avoid continuing phosphate binders when serum phosphate normalizes on intensive dialysis, as 40% of patients can discontinue binders entirely 1

Consequences Requiring Vigilance

Hypophosphatemia in dialysis patients causes serious complications including osteomalacia, fractures, rhabdomyolysis, cardiac arrhythmias, respiratory failure requiring prolonged mechanical ventilation (OR 1.81), and neurological dysfunction including reversible encephalopathy 1, 3, 4, 5