What are the causes and treatment options for hypercalcemia, particularly in patients with a history of kidney disease or those taking medications such as lithium or thiazide diuretics?

Causes of Hypercalcemia

Most Common Etiologies

Approximately 90% of hypercalcemia cases are caused by primary hyperparathyroidism (PHPT) or malignancy 1. The remaining 10% includes a diverse range of conditions that must be systematically evaluated.

Primary Hyperparathyroidism and Malignancy

• Primary hyperparathyroidism is the leading cause in ambulatory patients, characterized by autonomous PTH secretion leading to elevated or inappropriately normal PTH levels despite hypercalcemia 1, 2
• Malignancy-associated hypercalcemia is the second most common cause, particularly from multiple myeloma, breast cancer, and lymphoma 2
• Chronic renal failure with tertiary hyperparathyroidism (autonomous PTH secretion despite hypercalcemia) represents another important cause 3

Medication-Induced Hypercalcemia

• Thiazide diuretics are a well-established cause, with severe cases reaching calcium levels as high as 19.8 mg/dL reported 4
• Lithium commonly causes hypercalcemia by altering the calcium-sensing receptor set point 2, 3
• Calcium and vitamin D supplements can cause hypercalcemia, particularly when combined with thiazides 4
• Calcitriol and vitamin D analogues (such as paricalcitol) cause hypercalcemia in 22.6-43.3% of patients in clinical trials 5
• Patiromer (potassium binder) can cause hypercalcemia due to its calcium-sorbitol counterion 5

Vitamin D-Related Causes

• Granulomatous diseases (particularly sarcoidosis) cause hypercalcemia through excessive production of 1,25-dihydroxyvitamin D by activated macrophages 1, 3
• Vitamin D intoxication from excessive supplementation 1, 3
• Some lymphomas produce 1,25-dihydroxyvitamin D 1, 3

Other Endocrine and Metabolic Causes

• Thyrotoxicosis increases bone turnover and calcium release 3
• Immobilization reduces mechanical stress on bone, leading to increased resorption 1, 3
• Familial hypocalciuric hypercalcemia (genetic disorder affecting calcium-sensing receptor) 3

Emerging and Rare Causes

• Denosumab discontinuation causes rebound hypercalcemia 1
• Immune checkpoint inhibitors (less than 1% of cases) 1
• SGLT-2 inhibitors (sodium-glucose cotransporter 2 inhibitors) 1
• Milk-alkali syndrome from excessive calcium carbonate intake 3

Diagnostic Approach

Initial Laboratory Evaluation

Measure intact PTH as the single most important initial test to distinguish PTH-dependent from PTH-independent causes 1, 2.

• Elevated or normal PTH (with hypercalcemia) indicates primary hyperparathyroidism or tertiary hyperparathyroidism in CKD patients 1, 2
• Suppressed PTH (<20 pg/mL) indicates PTH-independent hypercalcemia, most commonly malignancy 1, 2

Comprehensive Workup

• Measure albumin-corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium + 0.8 × [4.0 - Serum albumin] 6
• Alternatively, measure ionized calcium to avoid pseudo-hypercalcemia from hemolysis or improper sampling 5, 3
• Check 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy in vitamin D-mediated conditions 5
• Measure PTHrP (parathyroid hormone-related protein) if PTH is suppressed and malignancy is suspected 5
• Assess renal function (creatinine, BUN) as CKD significantly alters calcium metabolism 5
• Check phosphorus and magnesium levels 5

Medication History

Obtain detailed history of thiazide diuretics, lithium, calcium supplements (>500 mg/day), vitamin D supplements (>400 IU/day), and vitamin A intake 5.

Treatment Based on Severity and Etiology

Mild Hypercalcemia (Total Calcium <12 mg/dL)

• Usually asymptomatic but may cause fatigue and constipation in approximately 20% of patients 1
• Does not typically require acute intervention 1
• If due to PHPT in patients >50 years with calcium <1 mg above upper normal limit and no skeletal or kidney disease, observation with monitoring is appropriate 1
• Discontinue causative medications (thiazides, lithium, calcium/vitamin D supplements) 4

Severe Hypercalcemia (Total Calcium ≥14 mg/dL or Ionized Calcium ≥10 mg/dL)

Initiate aggressive IV normal saline hydration immediately, targeting urine output of 100-150 mL/hour, followed by IV zoledronic acid 4 mg infused over at least 15 minutes 5, 6.

Step 1: Aggressive Hydration

• Administer IV normal saline to correct hypovolemia and promote calciuresis 5, 6, 1
• Target urine output 100-150 mL/hour or approximately 2 L/day 6
• Monitor fluid status carefully to avoid overhydration, especially in patients with cardiac or renal failure 5, 6
• Do not use loop diuretics before correcting hypovolemia, as this worsens volume contraction 6
• Loop diuretics (furosemide) should only be used after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 5

Step 2: Bisphosphonate Therapy

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is the preferred bisphosphonate due to superior efficacy compared to pamidronate 5, 6, 1
• Normalizes calcium in 50% of patients by day 4 5
• Do not delay bisphosphonate therapy in moderate to severe hypercalcemia 5, 6
• Adjust dose for creatinine clearance <60 mL/min 5
• Monitor serum creatinine before each dose and withhold if renal deterioration occurs 5

Step 3: Calcitonin (Bridge Therapy)

• Calcitonin-salmon 4 International Units/kg every 12 hours subcutaneously or intramuscularly provides rapid onset within hours but limited efficacy 5, 7
• Can increase to 8 International Units/kg every 12 hours if response inadequate after 1-2 days 7
• Maximum dose: 8 International Units/kg every 6 hours 7
• Use as bridge therapy until bisphosphonates take effect (typically 2-4 days) 5
• Tachyphylaxis develops within 48-72 hours, limiting long-term utility 5

Step 4: Etiology-Specific Therapies

For vitamin D-mediated hypercalcemia (sarcoidosis, granulomatous diseases, some lymphomas):

• Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent is the primary treatment 5
• Corticosteroids reduce excessive intestinal calcium absorption 5, 1
• Allow 3-6 months to demonstrate responsiveness 5
• Target lowest effective dose ≤10 mg/day to minimize toxicity 5
• If unable to wean below 10 mg/day after 3-6 months, add methotrexate as steroid-sparing agent 5

For bisphosphonate-refractory hypercalcemia:

• Denosumab 120 mg subcutaneously lowers calcium in 64% of patients within 10 days 5
• Higher risk of hypocalcemia compared to bisphosphonates; correct hypocalcemia before initiating and monitor closely 5
• Administer oral calcium supplement 500 mg plus vitamin D 400 IU daily during treatment 5

For severe hypercalcemia with renal failure:

• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L or 1.5-2.0 mEq/L) is reserved for severe cases complicated by renal insufficiency or oliguria 5, 6
• Do not use low-calcium dialysate for prolonged periods without treating primary cause, as it causes severe bone demineralization 6

Special Considerations in CKD Patients

For CKD patients with hypercalcemia and low PTH (adynamic bone disease):

• Immediately discontinue all calcium-based phosphate binders 5
• Stop all vitamin D analogs (calcitriol, paricalcitol) and vitamin D supplements 5
• Consider lower dialysate calcium concentration (1.5-2.0 mEq/L) to stimulate PTH and increase bone turnover 5
• Allow intact PTH to rise to at least 100 pg/mL to avoid low-turnover bone disease 5
• Monitor carefully; if PTH exceeds 300 pg/mL, dialysate calcium may need adjustment 5
• Target corrected calcium 8.4-9.5 mg/dL, preferably at lower end of range 5

Critical pitfall: Adynamic bone in CKD patients cannot modulate calcium appropriately, leading to marked hypercalcemia with minimal calcium loading and increased risk of metastatic calcification and calciphylaxis 8.

Monitoring Protocol

• Check serum calcium, renal function, and electrolytes every 6-12 hours during acute phase 5
• Obtain ECG to assess for QT interval changes, though these are variable 6
• Monitor for symptomatic hypocalcemia (tetany, seizures) following treatment; asymptomatic hypocalcemia does not require intervention 5

Definitive Management

• Parathyroidectomy is indicated for tertiary hyperparathyroidism (persistent hypercalcemic hyperparathyroidism despite optimized medical therapy) 5
• Treat underlying malignancy when possible, as hypercalcemia of malignancy carries poor prognosis with median survival approximately 1 month 5

Critical Pitfalls to Avoid

• Never rely on corrected calcium instead of ionized calcium in critically ill patients, as it can lead to inaccurate diagnosis 5
• Do not restrict calcium intake excessively without medical supervision, as this can worsen bone disease 5
• Avoid NSAIDs and IV contrast media in patients with renal impairment to prevent further kidney deterioration 5
• Do not use vitamin D supplements in patients with hypercalcemia, particularly in early childhood 5
• Patients on thiazide diuretics should have electrolytes frequently checked, especially those on calcium supplements 4