What is the differential diagnosis for non-small cell lung cancer presenting with hyponatremia, hypokalemia, hypomagnesemia, hypocalcemia, and hyperphosphatemia in a patient on Tagrisso (osimertinib) and tenofovir (tenofovir disoproxil fumarate)?

Differential Diagnosis for NSCLC with Multiple Electrolyte Abnormalities on Tagrisso and Tenofovir

The most likely diagnosis is tenofovir-induced Fanconi syndrome (proximal renal tubular acidosis type II), which explains the entire constellation of hypokalemia, hypomagnesemia, hypocalcemia, and hyperphosphatemia, while the hyponatremia is likely multifactorial from SIADH (paraneoplastic) and/or osimertinib-induced renal injury.

Primary Differential Considerations

1. Tenofovir-Induced Fanconi Syndrome (Most Likely)

• Tenofovir disoproxil fumarate causes proximal tubular dysfunction leading to urinary wasting of phosphate, potassium, magnesium, calcium, glucose, amino acids, and bicarbonate
• This single diagnosis explains hypokalemia, hypomagnesemia, hypocalcemia, and hyperphosphatemia (the latter from urinary phosphate wasting with secondary hyperparathyroidism)
• The pattern of multiple electrolyte losses with preserved or elevated serum phosphate is pathognomonic for proximal tubular dysfunction
• Key diagnostic features to confirm:
  • Urine phosphate wasting (elevated fractional excretion of phosphate >20%)
  • Urine potassium >20 mEq/L despite hypokalemia
  • Urine magnesium >24 mg/day despite hypomagnesemia
  • Glucosuria without hyperglycemia
  • Non-anion gap metabolic acidosis from bicarbonate wasting

2. Osimertinib-Induced Renal Injury (Contributing Factor)

• Osimertinib causes renal injury in 18.89% of patients, with most cases being transient but 5.8% developing sustained injury 1
• Renal injury typically manifests as decreased eGFR and proteinuria, occurring at a mean of 7.92 months after initiation 1
• Biopsy-proven acute tubular injury has been documented with osimertinib, which can exacerbate electrolyte abnormalities 2
• Age ≥60 years and baseline renal injury are independent risk factors for sustained osimertinib-related renal injury 1
• This likely compounds the tenofovir toxicity and may contribute to hyponatremia through impaired renal sodium handling

3. Paraneoplastic SIADH (Explaining Hyponatremia)

• Hyponatremia occurs in 1% of NSCLC cases (compared to 10-45% in small cell lung cancer) 3
• SIADH from excess arginine vasopressin production by tumor cells is the primary mechanism 3
• Hyponatremia is associated with shortened survival in NSCLC and serves as a negative prognostic marker 4
• Diagnostic criteria for SIADH:
  • Hyponatremia with hypoosmolality (<280 mOsm/kg)
  • Inappropriately high urine osmolality (>100 mOsm/kg)
  • Urine sodium >40 mEq/L
  • Absence of volume depletion, hypothyroidism, or adrenal insufficiency 3

4. Platinum-Based Chemotherapy Effects (If Previously Treated)

• If the patient received prior cisplatin or carboplatin, this can cause persistent electrolyte wasting including hypomagnesemia, hypokalemia, hypophosphatemia, and hypocalcemia 5
• Platinum-induced tubular damage can persist long after chemotherapy completion
• However, this would not explain hyperphosphatemia, making tenofovir-induced Fanconi syndrome more likely

Secondary Considerations to Exclude

5. Central Adrenal Insufficiency

• Would present with hyponatremia, hypokalemia, and hypotension 6
• Key distinguishing features:
  • Low morning cortisol (<3 μg/dL confirms diagnosis)
  • Low or inappropriately normal ACTH
  • Often accompanied by low TSH (central hypothyroidism) 6
• Does not explain hypomagnesemia, hypocalcemia, or hyperphosphatemia, making this less likely as the primary diagnosis

6. Malnutrition-Related Electrolyte Depletion

• Severe cancer-associated malnutrition can cause hyponatremia with loss of intracellular water and solutes 3
• Would typically present with hypophosphatemia (not hyperphosphatemia) during refeeding
• Does not explain the specific pattern of tubular electrolyte wasting

Diagnostic Algorithm

Immediate laboratory evaluation:

• Renal function: Serum creatinine, eGFR, BUN
• Urine studies: Spot urine for sodium, potassium, magnesium, phosphate, calcium, glucose, protein, and creatinine to calculate fractional excretions
• Serum osmolality and urine osmolality to evaluate SIADH
• Arterial blood gas to assess for metabolic acidosis (Fanconi syndrome)
• Morning cortisol and ACTH if hypotension or other signs of adrenal insufficiency present 6
• Parathyroid hormone (PTH) to evaluate calcium-phosphate metabolism

Diagnostic confirmation:

• Fanconi syndrome confirmed by: Fractional excretion of phosphate >20%, urine potassium >20 mEq/L, urine magnesium >24 mg/day, glucosuria without hyperglycemia, non-anion gap metabolic acidosis
• SIADH confirmed by: Serum osmolality <280 mOsm/kg, urine osmolality >100 mOsm/kg, urine sodium >40 mEq/L, euvolemic status 3
• Osimertinib renal injury confirmed by: eGFR <60 mL/min/1.73m² and/or proteinuria, temporal relationship to drug initiation 1

Management Priorities

For tenofovir-induced Fanconi syndrome:

• Discontinue tenofovir immediately and switch to alternative antiretroviral if indicated (e.g., tenofovir alafenamide has lower renal toxicity)
• Aggressive electrolyte repletion: IV magnesium sulfate, potassium chloride, calcium gluconate
• Oral phosphate supplementation if needed
• Monitor for renal recovery over 4-6 weeks

For osimertinib-related renal injury:

• Reduce osimertinib dose from 80 mg to 40 mg daily if eGFR declines or proteinuria develops 2
• Regular monitoring of renal function every 2-4 weeks 1
• Most cases recover with dose reduction (mean recovery time 4.21 months) 1

For SIADH-related hyponatremia:

• Fluid restriction <1 L/day for mild asymptomatic hyponatremia 3
• 3% hypertonic saline IV for severe symptomatic hyponatremia (<120 mEq/L) 3
• Correction rate must not exceed 0.5 mEq/L/hour or 10-12 mEq/L/day to prevent osmotic demyelination syndrome 3, 6

Critical Pitfalls to Avoid

• Do not attribute all electrolyte abnormalities to cancer alone—the specific pattern of hypokalemia, hypomagnesemia, hypocalcemia, and hyperphosphatemia strongly suggests drug-induced tubular dysfunction
• Do not continue tenofovir if Fanconi syndrome is confirmed—permanent renal damage can occur
• Do not correct hyponatremia too rapidly—risk of osmotic demyelination syndrome is high with correction >10-12 mEq/L/day 3, 6
• Do not assume osimertinib is safe for kidneys—18.89% of patients develop renal injury, requiring regular monitoring 1
• Do not overlook adrenal insufficiency if hypotension is present—check morning cortisol and ACTH 6