What is the initial workup and treatment for a patient with hypercalcemia by a nephrologist?

Nephrologist's Workup for Hypercalcemia

Immediately measure serum intact PTH, corrected calcium (or ionized calcium), albumin, creatinine, phosphorus, magnesium, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D to determine the underlying etiology and guide treatment. 1

Initial Laboratory Panel

The diagnostic workup must include:

• Intact parathyroid hormone (iPTH) - This is the single most important test that distinguishes PTH-dependent from PTH-independent causes 1, 2
• Corrected calcium using the formula: Corrected calcium (mg/dL) = Total calcium (mg/dL) - 0.8 × [Albumin (g/dL) - 4], or preferably measure ionized calcium directly (normal: 4.65-5.28 mg/dL) 1, 3
• Serum creatinine and estimated GFR to assess kidney function, as CKD significantly alters calcium metabolism and PTH interpretation 3, 1
• Phosphorus - typically low-normal in primary hyperparathyroidism 3
• Magnesium - to identify electrolyte deficiencies that require correction 1
• 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D - measuring both together provides critical diagnostic information, as their relationship distinguishes between causes 3, 1
• PTHrP (parathyroid hormone-related protein) if PTH is suppressed, to evaluate for malignancy-associated hypercalcemia 1

Critical Technical Considerations

• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C 3
• PTH assays vary up to 47% between different generations, so use assay-specific reference values 3
• Biological variation of PTH is substantial (20% in healthy individuals), so differences must exceed 54% to be clinically significant 3

Severity Stratification

Classify hypercalcemia severity to guide urgency of intervention 1:

• Mild: 10-11 mg/dL (usually asymptomatic, though 20% may have constitutional symptoms like fatigue and constipation) 2
• Moderate: 11-12 mg/dL (presents with polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain) 1
• Severe: >14 mg/dL (mental status changes, bradycardia, hypotension, severe dehydration, acute renal failure) 3, 2

Diagnostic Algorithm Based on PTH Level

Elevated or Inappropriately Normal PTH (PTH-Dependent)

This pattern confirms primary hyperparathyroidism 3, 2:

• Expect elevated or inappropriately normal PTH with hypercalcemia 3
• Serum phosphorus typically low-normal 3
• Hyperchloremic metabolic acidosis may be present 1
• Exclude vitamin D deficiency first - measure 25-hydroxyvitamin D, as deficiency causes secondary hyperparathyroidism and must be ruled out before diagnosing primary hyperparathyroidism 3
• PTH reference values are 20% lower in vitamin D-replete individuals 3
• Consider preoperative localization imaging with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT only if surgery is planned - do not order parathyroid imaging before confirming biochemical diagnosis, as imaging is for surgical planning, not diagnosis 3

Surgical indications for primary hyperparathyroidism 3, 1:

• Corrected calcium >1 mg/dL above upper limit of normal
• Age <50 years
• Impaired kidney function (GFR <60 mL/min/1.73 m²)
• Osteoporosis on bone density scan
• History of nephrolithiasis or nephrocalcinosis
• Hypercalciuria on 24-hour urine calcium or spot urine calcium/creatinine ratio

Suppressed PTH (<20 pg/mL) (PTH-Independent)

This pattern indicates causes other than primary hyperparathyroidism 2, 4:

Measure PTHrP 1:

• Elevated PTHrP = malignancy-associated hypercalcemia (occurs in 10-25% of lung cancer patients, most commonly squamous cell carcinoma, with median survival approximately 1 month) 3, 5
• Decreased 25-hydroxyvitamin D is expected as hypercalcemia suppresses PTH, which normally stimulates 1,25-dihydroxyvitamin D production 3

Evaluate vitamin D levels 1:

• Elevated 1,25-dihydroxyvitamin D with low 25-hydroxyvitamin D = granulomatous diseases (sarcoidosis, tuberculosis) or lymphomas, where increased 1α-hydroxylase activity in granulomas converts 25-OH to 1,25-(OH)2 vitamin D 3
• Elevated 25-hydroxyvitamin D = vitamin D intoxication 1

Additional Renal-Specific Assessments

As a nephrologist, include these evaluations 3, 1:

• 24-hour urine calcium or spot urine calcium/creatinine ratio to assess hypercalciuria and distinguish familial hypocalciuric hypercalcemia 3
• Renal ultrasonography to assess for nephrocalcinosis or kidney stones 3
• Bone density scan if chronic hyperparathyroidism is suspected 3

Medication Review

Immediately identify and discontinue causative medications 3, 1:

• Calcium supplements (>500 mg/day)
• Vitamin D supplements (>400 IU/day) - discontinue all forms if calcium exceeds 10.2 mg/dL 3
• Thiazide diuretics - switch to alternative antihypertensive 3
• Lithium - consider alternative mood stabilizer
• Calcium-based phosphate binders in CKD patients - reduce or discontinue if corrected calcium exceeds 10.2 mg/dL 3
• Calcitriol or vitamin D analogues (paricalcitol) - cause hypercalcemia in 22.6-43.3% of patients 6

Immediate Management Based on Severity

Mild Hypercalcemia (10-11 mg/dL)

• Ensure adequate oral hydration 3
• Discontinue calcium supplements, vitamin D, and thiazide diuretics 3
• Monitor serum calcium every 3 months for patients with GFR >30 mL/min/1.73 m² 3
• Maintain normal calcium intake (1000-1200 mg/day), avoiding high or low calcium diets 3

Moderate to Severe Hypercalcemia (>11 mg/dL)

Step 1: Aggressive IV Hydration 1, 7:

• Administer IV normal saline immediately to correct hypovolemia and promote calciuresis
• Target urine output ≥100-150 mL/hour
• Use balanced crystalloids over 0.9% saline when possible to avoid hyperchloremic metabolic acidosis 6
• Loop diuretics (furosemide) only after volume repletion in patients with renal or cardiac insufficiency to prevent fluid overload 1, 8

Step 2: IV Bisphosphonates 1, 8:

• Zoledronic acid 4 mg IV infused over no less than 15 minutes is preferred over pamidronate due to superior efficacy 1, 6, 8
• Normalizes calcium in 50% of patients by day 4 6
• Do not use doses >4 mg for initial treatment 6
• Dose adjustments required for creatinine clearance <60 mL/min 1, 8
• Monitor serum creatinine before each dose 6, 8
• Contraindicated in severe renal impairment (creatinine clearance <30 mL/min) 8

Step 3: Adjunctive Therapy for Severe Symptomatic Cases 1:

• Calcitonin 100 IU subcutaneously or intramuscularly for immediate short-term management while waiting for bisphosphonates to take effect (provides rapid onset within hours but limited efficacy) 1, 6, 7
• Tachyphylaxis develops quickly, limiting usefulness beyond 48 hours 4

Cause-Specific Treatment

Vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, granulomatous disorders) 1, 6:

• Glucocorticoids are primary treatment: Prednisone 20-40 mg/day orally or methylprednisolone IV equivalent 6
• Allow 3-6 months to demonstrate responsiveness 6
• Target lowest effective dose ≤10 mg/day to minimize toxicity 6

Refractory hypercalcemia or renal impairment 1, 6:

• Denosumab 120 mg subcutaneously for bisphosphonate-refractory cases (lowers calcium in 64% of patients within 10 days) 6
• Hemodialysis with calcium-free or low-calcium dialysate (1.25-1.50 mmol/L) for severe hypercalcemia complicated by kidney failure 1, 6, 5

Critical Pitfalls to Avoid

• Never order parathyroid imaging before confirming biochemical diagnosis - imaging is for surgical planning, not diagnosis 3
• Do not rely on corrected calcium alone - measure ionized calcium for definitive assessment to avoid pseudo-hypercalcemia 3, 6
• Measure BOTH 25-hydroxyvitamin D AND 1,25-dihydroxyvitamin D together for diagnostic accuracy 6
• Avoid loop diuretics before complete volume repletion - use only in renal or cardiac insufficiency 1, 8
• Do not supplement vitamin D until hypercalcemia resolves 3
• Avoid NSAIDs and IV contrast in patients with renal impairment to prevent further kidney deterioration 6
• Correct hypocalcemia before initiating bisphosphonate therapy and monitor calcium closely, especially with denosumab which carries higher risk 6, 8
• Perform preventive dental examination before starting bisphosphonates and avoid invasive dental procedures during treatment due to osteonecrosis of the jaw risk 8

Monitoring During Treatment

• Monitor serum calcium, creatinine, phosphorus, magnesium, and potassium every 6-12 hours during acute phase 1, 6
• Watch for bisphosphonate complications: renal toxicity and osteonecrosis of the jaw 8
• If vitamin D supplementation is restarted after calcium normalizes, measure calcium monthly for first 3 months 3