What are the next steps in evaluating and managing a 64‑year‑old woman with stage 3 chronic kidney disease, hypertension, heart failure with reduced ejection fraction, severe left‑ventricular hypertrophy, diastolic dysfunction, active smoker, and mild hypercalcemia (total calcium 11.5 mg/dL, ionized calcium high‑normal, intact parathyroid hormone low‑normal, 25‑hydroxyvitamin D insufficient, phosphorus low‑normal)?

Management of Hypercalcemia in a 64-Year-Old Woman with Stage 3 CKD and Heart Failure

Immediately discontinue any calcium-based phosphate binders and vitamin D supplements, as the combination of mild hypercalcemia (total calcium 11.5 mg/dL) with low-normal PTH (39 pg/mL) and insufficient vitamin D (29 ng/mL) suggests non-PTH-mediated hypercalcemia that requires urgent evaluation for malignancy before any other interventions. 1

Immediate Diagnostic Workup

Your patient's biochemical profile is concerning and requires urgent clarification:

• Rule out malignancy first: With total calcium 11.5 mg/dL, ionized calcium 6.3 mg/dL (high-normal to elevated), and a suppressed PTH of 39 pg/mL, this pattern is inconsistent with primary hyperparathyroidism and raises concern for hypercalcemia of malignancy, particularly given her smoking history. 2

• Order PTHrP (parathyroid hormone-related protein): This is essential to identify humoral hypercalcemia of malignancy, which commonly occurs in squamous cell lung cancer (highly relevant given active smoking) or genitourinary malignancies. 3

• Obtain chest imaging: A chest CT is warranted given the smoking history and the biochemical pattern suggesting possible paraneoplastic syndrome. 3

• Check serum protein electrophoresis and free light chains: Multiple myeloma can present with hypercalcemia and suppressed PTH. 3

Critical Interpretation of Laboratory Values

The biochemical constellation is atypical and demands careful analysis:

• PTH of 39 pg/mL is inappropriately low for a calcium of 11.5 mg/dL—in primary hyperparathyroidism, PTH would be elevated or high-normal despite hypercalcemia. 1, 4

• Vitamin D insufficiency (29 ng/mL) paradoxically coexists with hypercalcemia, which further argues against vitamin D intoxication and points toward a PTH-independent mechanism. 5, 1

• Phosphorus of 2.7 mg/dL is low-normal, which can occur in both primary hyperparathyroidism and malignancy-associated hypercalcemia. 4

• The calcium-phosphorus product is 31 mg²/dL² (11.5 × 2.7), which is well below the concerning threshold of 55 mg²/dL² but still requires monitoring. 1

Acute Management Considerations in the Context of HFrEF

Managing hypercalcemia in a patient with severe heart failure (HFrEF with severe LVH and diastolic dysfunction) presents a delicate balance:

• Avoid aggressive IV hydration: While standard hypercalcemia management typically involves vigorous IV saline (200-300 mL/hour), this patient's HFrEF with severe LVH makes her extremely vulnerable to volume overload and acute decompensation. 5, 2

• Use gentle IV hydration only if clinically dehydrated: If signs of dehydration are present, administer IV fluids cautiously at 75-100 mL/hour with close monitoring of volume status, daily weights, and lung examination. 5, 2

• Consider loop diuretics with caution: If hypercalcemia management requires calciuresis, furosemide can be used but only after adequate hydration and with careful monitoring of renal function (current creatinine 1.13, eGFR 54). 5

• Avoid bisphosphonates initially: Zoledronic acid and other bisphosphonates carry nephrotoxicity risk and should be reserved for confirmed malignancy-associated hypercalcemia after ruling out volume depletion. 5, 3

Cardiovascular Risk Stratification

The combination of CKD, hypercalcemia, and cardiac disease creates compounding risks:

• Hypercalcemia worsens LVH and diastolic dysfunction: Research demonstrates that calcium-phosphorus metabolism disorders directly contribute to cardiac structural damage and functional impairment in CKD patients. 6, 7

• Paradoxically, hypocalcemia also predicts diastolic dysfunction: Studies show that serum calcium ≤9.82 mg/dL independently predicts LV diastolic dysfunction (OR 8.81), suggesting a narrow therapeutic window in CKD patients. 8

• Monitor for arrhythmias: Hypercalcemia increases risk of arrhythmias and sudden death, particularly concerning given her severe LVH and history of diastolic dysfunction. 6

Medication Review and Adjustment

Conduct an immediate comprehensive medication audit:

• Stop all calcium-containing supplements immediately: This includes calcium carbonate, calcium citrate, or any multivitamins containing calcium. 1

• Discontinue vitamin D supplements: Any ergocalciferol, cholecalciferol, calcitriol, or paricalcitol must be stopped immediately. 1

• Review thiazide diuretics: If she is on hydrochlorothiazide or chlorthalidone, these reduce urinary calcium excretion and can worsen hypercalcemia—consider switching to loop diuretics. 5

• Assess lithium use: Though not mentioned, lithium can cause hypercalcemia with low-normal PTH and should be excluded from the medication history. 1

Monitoring Strategy During Workup

While awaiting malignancy workup results:

• Check serum calcium and ionized calcium weekly: More frequent monitoring (every 1-3 weeks) is required when hypercalcemia is present and interventions are being made. 1

• Monitor renal function closely: Check creatinine and eGFR every 1-2 weeks, as hypercalcemia can cause prerenal azotemia through polyuria and volume depletion. 9, 3

• Assess volume status at every encounter: Daily weights, orthostatic vital signs, and examination for edema versus dehydration are critical given the competing risks of HFrEF and hypercalcemia. 5, 10

• Repeat PTH if calcium normalizes: If calcium decreases to normal range, recheck PTH to determine if it appropriately rises, which would help differentiate the etiology. 4

CKD-Mineral Bone Disease Considerations

Despite stage 3a CKD (eGFR 54), her mineral metabolism is atypical:

• PTH of 39 pg/mL is lower than expected: For stage 3 CKD, PTH typically begins to rise above normal range (>65-70 pg/mL), so a value of 39 pg/mL is actually suppressed relative to her kidney function. 5, 4

• Do not treat PTH at this level: Current guidelines discourage aggressive PTH normalization in CKD, as modest elevation is an appropriate adaptive response; her low-normal PTH requires no intervention. 5, 1

• Vitamin D repletion is contraindicated: Despite vitamin D insufficiency (29 ng/mL), do NOT supplement vitamin D while hypercalcemia is present, as this will worsen the calcium elevation. 1

• Phosphate binders are not indicated: With phosphorus of 2.7 mg/dL (normal range), there is no indication for phosphate binders; if she is currently taking any, discontinue immediately. 1

Differential Diagnosis Priority

Based on the biochemical pattern, rank the following etiologies:

1. Malignancy-associated hypercalcemia (most likely): Suppressed PTH with hypercalcemia in an active smoker strongly suggests lung cancer with PTHrP secretion or osteolytic metastases. 3, 2

2. Granulomatous disease: Sarcoidosis or tuberculosis can cause hypercalcemia through extrarenal 1,25-dihydroxyvitamin D production, though less likely with vitamin D insufficiency. 3

3. Medication-induced: Calcium or vitamin D supplementation, thiazide diuretics, or lithium (if present in medication history). 1

4. Immobilization hypercalcemia: Less likely given she is ambulatory, but consider if mobility is significantly limited. 3

5. Primary hyperparathyroidism (unlikely): The suppressed PTH of 39 pg/mL argues strongly against this diagnosis. 2, 4

Critical Pitfalls to Avoid

• Do not assume this is benign CKD-related mineral disorder: The suppressed PTH with hypercalcemia is NOT consistent with secondary hyperparathyroidism of CKD and requires malignancy workup. 1, 4

• Do not aggressively hydrate without considering HFrEF: Standard hypercalcemia protocols calling for 3-4 liters of IV saline daily will precipitate acute heart failure in this patient. 5, 2

• Do not restart vitamin D after calcium normalizes at previous doses: If vitamin D contributed to hypercalcemia, reintroduction must be at substantially reduced doses with frequent calcium monitoring. 1

• Do not delay malignancy workup: With active smoking, suppressed PTH, and hypercalcemia, the pretest probability of malignancy is high and requires urgent evaluation. 3, 2

Nephrology Referral Threshold

Consider nephrology consultation for:

• Persistent hypercalcemia after stopping calcium/vitamin D: If calcium remains >10.5 mg/dL after 2-4 weeks of stopping supplements, specialist input is warranted. 5

• Declining renal function: If creatinine rises >20% or eGFR drops below 45 mL/min/1.73 m² (stage 3b), nephrology referral is indicated per guidelines. 5, 9

• Complex mineral metabolism management: Once malignancy is ruled out or treated, ongoing CKD-MBD management may benefit from nephrology expertise. 5

Smoking Cessation Urgency

• Prioritize smoking cessation counseling: Given the strong association between smoking and both lung malignancy (potential cause of hypercalcemia) and cardiovascular disease progression, intensive smoking cessation intervention is critical. 5

• Smoking accelerates CKD progression: Active smoking is an independent risk factor for faster decline in eGFR and should be addressed as part of comprehensive CKD management. 5