What are the causes of hypercalcemia in a patient with chronic kidney disease?

Causes of Hypercalcemia in CKD Patients

In CKD patients, hypercalcemia is most commonly iatrogenic—caused by excessive calcium-based phosphate binders, vitamin D analogs (calcitriol, paricalcitol), or vitamin D supplements—rather than the hyperparathyroidism typically seen in general populations. 1, 2, 3, 4

Medication-Induced Hypercalcemia (Most Common in CKD)

Calcium-Based Phosphate Binders

• Calcium acetate and calcium carbonate are the leading iatrogenic causes, with hypercalcemia occurring in 16% of patients within 3 months of treatment 2
• Patients with end-stage renal disease are particularly vulnerable when calcium supplements or calcium-based antacids are used concurrently with prescribed calcium binders 2
• The FDA label explicitly warns that overdose leads to progressive hypercalcemia requiring emergency measures 2

Vitamin D Compounds

• Calcitriol and vitamin D analogs (paricalcitol, alfacalcidol) cause hypercalcemia in 22.6-43.3% of CKD patients in clinical trials 1, 3, 4
• Excessive dosage induces hypercalcemia through increased intestinal calcium absorption 3, 4
• Even abrupt increases in dietary calcium (dairy products) can trigger hypercalcemia when patients are on these medications 3, 4
• Vitamin D intoxication from over-the-counter supplements is an increasingly recognized cause 1, 5

Other Medications

• Thiazide diuretics reduce urinary calcium excretion and cause hypercalcemia, especially when combined with calcitriol 3, 4, 5
• Patiromer (potassium binder) releases calcium in exchange for potassium in the colon 1
• Lithium therapy can cause hypercalcemia 5, 6

Tertiary (Persistent) Hyperparathyroidism

• This represents autonomous PTH secretion with hypercalcemia despite prior secondary hyperparathyroidism, biochemically distinct from secondary hyperparathyroidism which presents with hypocalcemia 7, 1
• Develops after prolonged secondary hyperparathyroidism when parathyroid glands become autonomously hyperplastic 7
• Associated with increased risk of graft failure and all-cause mortality post-transplant 7
• Parathyroidectomy is indicated when hypercalcemia persists despite optimized medical therapy 1

Post-Transplant Hypercalcemia

• Mineral metabolism disturbances are highly common after kidney transplantation and rarely resolve spontaneously 7
• Persistent hyperparathyroidism (with elevated or inappropriately normal PTH) causes hypercalcemia post-transplant 7
• The severity depends partly on pre-transplant management of mineral bone disorder 7
• Calcimimetics can correct high calcium levels but intervention thresholds remain undefined 7

Milk-Alkali Syndrome

• Persistent ingestion of calcium carbonate combined with vitamin D causes the triad of hypercalcemia, metabolic alkalosis, and acute kidney injury 8
• This is a reemerging cause of hypercalcemia in CKD patients treated for osteoporosis or iatrogenic hypoparathyroidism 8
• Particularly relevant in CKD where calcium-based phosphate binders are prescribed long-term 8

Malignancy-Associated Hypercalcemia

• While malignancy is a leading cause in the general population, it accounts for fewer cases in CKD patients compared to iatrogenic causes 5
• Multiple myeloma and bone metastases are the most relevant malignancies in CKD populations 1
• Critical diagnostic pitfall: C-terminal PTHrP assays accumulate in CKD and can be falsely elevated in normocalcemic CKD patients without malignancy 9
• Always request N-terminal PTHrP assays specifically when evaluating for humoral hypercalcemia of malignancy in advanced kidney disease 9

Less Common Causes in CKD

• Granulomatous diseases (sarcoidosis) cause excessive intestinal calcium absorption through extrarenal 1,25-dihydroxyvitamin D production 1, 5, 6
• Immobilization increases bone resorption, particularly in dialysis patients 3, 4, 5
• Thyrotoxicosis increases bone turnover 5, 6
• Familial hypocalciuric hypercalcemia (rare genetic disorder) 5, 6

Diagnostic Approach Specific to CKD

Immediate Medication Review

• Discontinue all calcium-based phosphate binders, vitamin D analogs, and vitamin D supplements immediately when hypercalcemia is detected 1
• Review thiazide diuretics, lithium, and other calcium-elevating medications 3, 4, 5

Laboratory Evaluation

• Measure ionized calcium rather than total calcium, as corrected calcium formulas are often inaccurate 1, 6
• Check intact PTH to distinguish PTH-dependent (elevated/normal PTH) from PTH-independent (suppressed PTH <20 pg/mL) causes 5, 6
• In CKD with hypercalcemia, PTH is typically suppressed, confirming iatrogenic or PTH-independent mechanisms 1
• Measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D together for diagnostic accuracy 1
• If malignancy suspected, specifically request N-terminal PTHrP (not C-terminal) to avoid false positives from renal accumulation 9

Common Pitfall

The most frequent diagnostic error is failing to recognize that C-terminal PTHrP assays are elevated in CKD patients without malignancy, leading to unnecessary cancer workups 9. Many commercial laboratories run C-terminal assays as first-line tests 9. This can delay appropriate treatment of the actual cause—usually medication-related 9.