What are the differential diagnoses for a 65-year-old female with type 2 diabetes mellitus (T2DM) and a history of heavy smoking, presenting with acute renal failure, hypercalcemia, and new-onset anemia?

Differential Diagnoses for Acute Renal Failure, Hypercalcemia, and New-Onset Anemia

Multiple myeloma is the primary diagnosis that must be ruled out immediately in this 65-year-old woman presenting with the classic triad of hypercalcemia, acute renal failure, and new-onset anemia. 1

Primary Differential Diagnosis

Multiple myeloma represents the leading concern when hypercalcemia, renal dysfunction, and anemia present together, forming part of the "CRAB" criteria (hypercalcemia, renal dysfunction, anemia, and bone lesions) that define end-organ damage in this malignancy. 1 This constellation occurs because:

• Hypercalcemia develops through increased osteoclastic bone resorption mediated by the malignant plasma cell clone, typically with serum M-protein ≥3 g/dL and/or bone marrow clonal plasma cells ≥10%. 1
• Renal failure occurs in 20-50% of myeloma patients, primarily from light chain cast nephropathy combined with hypercalcemia-induced volume depletion and direct nephrotoxicity. 2
• Anemia results from bone marrow infiltration by plasma cells and suppression of normal hematopoiesis, typically presenting with hemoglobin <10 g/dL or ≥2 g/dL below normal. 1, 2

The patient's age (65 years) and diabetes place her in a high-risk demographic, as multiple myeloma primarily affects elderly patients and diabetes prevalence reaches 21.6% in this age group. 3

Secondary Differential Diagnosis

Squamous cell lung cancer with hypercalcemia of malignancy must be considered given her heavy smoking history. 1 Key features include:

• Hypercalcemia occurs in 10-25% of lung cancer patients, most commonly with squamous cell histology, through parathyroid hormone-related protein (PTHrP) production. 1
• Median survival after hypercalcemia discovery is approximately 1 month, making urgent diagnosis essential. 1
• Renal failure develops from hypercalcemia-induced volume depletion and decreased glomerular filtration. 1
• Anemia of chronic disease accompanies advanced malignancy.

Additional Differential Considerations

Sarcoidosis can present with this triad, though less commonly. 4 This diagnosis features:

• Non-PTH mediated hypercalcemia through elevated 1,25-dihydroxyvitamin D levels produced by granulomas. 4
• Nonnecrotizing granulomatous inflammation on tissue biopsy. 4
• Elevated ACE and beta-2 microglobulin levels. 4
• Response to glucocorticoid therapy. 4

Primary hyperparathyroidism is less likely given the acute presentation with renal failure and anemia, as this typically presents with chronic, stable mild hypercalcemia in ambulatory patients. 5 However, it accounts for the majority of hypercalcemia in outpatients and should be considered if the clinical picture is more chronic than initially apparent. 5

Immediate Diagnostic Workup

Order the following tests immediately to differentiate between diagnoses:

For Multiple Myeloma Evaluation:

• Serum and urine protein electrophoresis with immunofixation. 1, 2
• Serum free light chain assay with kappa/lambda ratio. 1, 2
• Bone marrow biopsy with CD138 staining to quantify plasma cells (≥10% clonal plasma cells required for diagnosis). 2
• Complete skeletal survey or whole-body CT to identify lytic lesions. 1
• Complete blood count, serum calcium, creatinine, and β2-microglobulin. 2

For Hypercalcemia Differentiation:

• Serum intact PTH, PTHrP, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D. 1
• Calcium, albumin, phosphorus, and magnesium levels. 1
• Serum chloride (elevated chloride favors hyperparathyroidism). 5

For Lung Cancer Evaluation:

• Chest CT scan (not just X-ray) to evaluate for masses, given heavy smoking history. 1
• Consider bronchoscopy if imaging suggests malignancy. 4

For Sarcoidosis Evaluation (if initial workup negative):

• ACE levels and beta-2 microglobulin. 4
• Chest CT for lymphadenopathy or parenchymal disease. 4
• Bronchoscopy with transbronchial biopsy if suspicion remains high. 4

Immediate Management Priorities

Begin aggressive treatment for hypercalcemia immediately while diagnostic workup proceeds:

• Administer IV normal saline hydration (>3 L/24h) as first-line treatment regardless of underlying cause. 1, 2
• Give bisphosphonates (zoledronic acid 4 mg IV over 15 minutes) for symptomatic or severe hypercalcemia (>14 mg/dL). 1
• Avoid nephrotoxins and contrast studies without adequate hydration to protect remaining renal function. 2
• Monitor renal function closely as serum calcium levels decrease, since renal function typically improves simultaneously with calcium correction. 6

Critical Clinical Pitfalls

Do not delay diagnostic workup based on initial imaging results. Chest X-ray may be normal in early sarcoidosis or small lung cancers; CT imaging is essential. 4

Do not rely solely on PTH levels to exclude hyperparathyroidism. Multivariate discriminant analysis using serum calcium, phosphorus, chloride, and hematocrit achieves 95-98% accuracy and is more economical than PTH alone. 5

Do not assume hypocalcemia in acute renal failure. While hypocalcemia is more common, the presence of hypercalcemia with acute renal failure strongly indicates underlying comorbidity requiring immediate investigation. 6

Do not delay systemic therapy if multiple myeloma is confirmed. The combination of CRAB criteria indicates active disease requiring immediate treatment, and median survival with untreated hypercalcemia of malignancy is only 1 month. 1