How to treat hypercalcemia in a patient with End-Stage Renal Disease (ESRD)?

Treatment of Hypercalcemia in ESRD Patients

In ESRD patients with hypercalcemia, immediately discontinue or reduce calcium-based phosphate binders and vitamin D analogues, lower dialysate calcium concentration to 1.25 mmol/L, and consider pamidronate for severe or malignancy-related hypercalcemia. 1, 2

Immediate Interventions

Discontinue Calcium Loading

• Stop or reduce calcium-based phosphate binders (calcium carbonate, calcium acetate) as these are the most common iatrogenic cause of hypercalcemia in ESRD. 1
• Discontinue calcitriol and vitamin D analogues, which increase intestinal calcium absorption and can worsen hypercalcemia. 1
• The 2017 KDIGO guideline explicitly recommends avoiding inappropriate calcium loading across all CKD stages, with particular emphasis on preventing hypercalcemia. 1

Adjust Dialysate Calcium

• Lower dialysate calcium concentration to 1.25 mmol/L to create a negative calcium gradient and remove calcium during dialysis sessions. 1, 3
• This lower concentration promotes calcium removal from the patient into the dialysate. 1

Intensify Dialysis

• Increase dialysis frequency or duration to enhance calcium removal, particularly effective in patients with tumoral calcinosis or severe hypercalcemia. 4
• Daily hemodialysis has been shown to achieve complete remission of severe calcium-phosphate disorders within weeks to months. 4

Pharmacologic Management for Severe or Refractory Cases

Bisphosphonates (Pamidronate)

• Pamidronate is safe and effective for treating severe hypercalcemia in ESRD patients on dialysis, particularly when secondary to malignancy. 2
• Dosing may require adjustment with re-dosing intervals of approximately 8 weeks as needed. 2
• This contradicts older teaching that bisphosphonates are contraindicated in ESRD—recent evidence demonstrates safety when used judiciously. 2

Calcitonin

• May be used as a temporizing measure, though effectiveness is limited and hypercalcemia often persists despite calcitonin therapy. 2

Switch Phosphate Binder Strategy

Non-Calcium Based Binders

• Replace calcium-based binders with sevelamer (calcium- and aluminum-free) to control phosphate without calcium loading. 1
• Sevelamer effectively controls serum phosphorus while avoiding hypercalcemia and has been shown to reduce progression of vascular calcification compared to calcium-based binders. 1, 5
• Lanthanum carbonate is an alternative non-calcium binder, though long-term safety data in children and accumulation concerns exist. 1

When to Use Non-Calcium Binders

• The KDOQI guideline states that if total intestinal calcium load becomes excessive or hypercalcemia exists with calcium-containing binders, these should be reduced or replaced by calcium- and aluminum-free binders. 1
• Sevelamer has been proven in randomized trials to control phosphorus equally well as calcium-based binders while causing significantly fewer hypercalcemia episodes. 1

Monitoring Parameters

Serial Assessments Required

• Monitor serum calcium, phosphate, and PTH together as therapeutic maneuvers affecting one variable often have unintended effects on others. 1
• Rising PTH and alkaline phosphatase suggest inadequate calcium replacement if hypocalcemia develops after aggressive treatment. 6, 3
• The 2017 KDIGO guideline emphasizes that treatment approaches should be based on serial assessments of these biochemical variables taken together, not single values. 1

Critical Pitfalls to Avoid

Calcium-Phosphate Product

• Avoid creating an elevated calcium-phosphate product, which promotes vascular and soft tissue calcification. 1, 5
• Hypercalcemia episodes are significantly more frequent with calcium-based binders compared to sevelamer. 1

Vitamin D Analogues

• Do not routinely use calcitriol or vitamin D analogues in non-dialysis CKD patients due to increased hypercalcemia risk. 1
• In dialysis patients with hypercalcemia, these agents must be discontinued or significantly reduced. 1

Bisphosphonate Considerations

• While pamidronate is safe in ESRD on dialysis, antiresorptive agents can exacerbate low bone turnover and denosumab may induce significant hypocalcemia. 1
• Bone biopsy should be considered before initiating antiresorptive therapy to determine underlying bone phenotype. 1

Special Considerations

Malignancy-Related Hypercalcemia

• Pamidronate is particularly effective for sustained hypercalcemia secondary to bone metastases in ESRD patients. 2
• Standard measures including calcitonin may fail, making bisphosphonates the definitive treatment. 2

Tertiary Hyperparathyroidism

• Severe refractory hypercalcemia with tertiary hyperparathyroidism may ultimately require parathyroidectomy. 1, 4
• Medical management should be optimized first, but surgical intervention becomes necessary when medical therapy fails. 1