Can pembrolizumab (pembrolizumab) cause hyponatremia in patients with a history of cancer, particularly those with metastasis or pre-existing renal issues?

Pembrolizumab-Induced Hyponatremia

Yes, pembrolizumab can cause hyponatremia, with the mechanism primarily involving immune-mediated endocrinopathies (adrenal insufficiency and hypothyroidism) and less commonly immune-mediated nephritis. 1, 2

Incidence and Clinical Evidence

• Hyponatremia is recognized as one of the most common grade ≥3 treatment-related adverse events with pembrolizumab, occurring alongside arthralgia in clinical trials of patients with bladder cancer. 1
• The overall incidence of renal toxicities with pembrolizumab is approximately 1.77%, though this likely underestimates electrolyte disturbances that may not trigger nephrology referral. 3

Mechanisms of Pembrolizumab-Induced Hyponatremia

Primary Mechanism: Immune-Mediated Endocrinopathies

The most common pathway is through immune checkpoint inhibitor-induced endocrine dysfunction, specifically adrenal insufficiency and hypothyroidism. 2

• Adrenal insufficiency causes hyponatremia through:

  • Loss of cortisol-mediated suppression of antidiuretic hormone (ADH), leading to syndrome of inappropriate ADH secretion (SIADH)
  • Direct mineralocorticoid deficiency (though less common with secondary adrenal insufficiency)
  • Pembrolizumab-induced adrenalitis can present acutely with severe hyponatremia requiring high-dose corticosteroid therapy 4

• Hypothyroidism contributes through:

  • Reduced cardiac output and glomerular filtration rate
  • Increased ADH secretion
  • Both mechanisms can coexist in the same patient 2

Secondary Mechanism: Immune-Mediated Nephritis

Direct renal injury from pembrolizumab can cause hyponatremia through salt-wasting nephropathy. 5, 3

• Acute interstitial nephritis (AIN) is the most commonly reported renal toxicity with pembrolizumab, occurring in approximately one-third of patients with renal involvement 3

• Other renal manifestations include:

  • Acute tubular injury (ATI) - seen in approximately 40% of biopsy-proven cases 3
  • Minimal change disease with associated tubular dysfunction 3
  • Rapid-onset nephritis can occur even after the first infusion 6

• Renal tubular dysfunction from any of these lesions can impair sodium reabsorption, leading to hyponatremia through renal salt wasting 3

Clinical Presentation Timeline

Endocrine-mediated hyponatremia typically develops after multiple cycles (median 9 months of therapy), while nephritis-related cases can occur earlier, even after the first infusion. 6, 3, 4

• Severe hyponatremia from adrenal insufficiency often presents with concomitant hypotension and may require vasopressor support 4
• Nephritis-related hyponatremia usually presents with acute kidney injury (elevated creatinine) and may have associated proteinuria 5, 3

Diagnostic Approach

When hyponatremia develops in a patient on pembrolizumab:

1. Immediately assess for adrenal insufficiency:

   • Morning cortisol level
   • ACTH stimulation test if cortisol is borderline
   • Clinical signs: hypotension, hyperkalemia, hypoglycemia 2, 4

2. Evaluate thyroid function:

   • TSH and free T4
   • Hypothyroidism can coexist with adrenal insufficiency 2

3. Assess renal function:

   • Serum creatinine and trend
   • Urinalysis for proteinuria, hematuria, pyuria
   • Fractional excretion of sodium to distinguish SIADH from salt-wasting 3, 4

4. Consider kidney biopsy if:

   • Acute kidney injury is present without clear endocrine cause
   • Significant proteinuria develops
   • Renal function does not improve with endocrine replacement 3

Management Strategy

For endocrine-mediated hyponatremia:

• Initiate high-dose corticosteroids (hydrocortisone 100 mg IV every 8 hours or equivalent) for suspected adrenal insufficiency 4
• Add thyroid hormone replacement if hypothyroidism is confirmed 2
• Pembrolizumab can often be continued if endocrine function is adequately replaced 7, 8

For nephritis-mediated hyponatremia:

• Discontinue pembrolizumab immediately 5, 3
• Initiate corticosteroids (prednisone 1 mg/kg/day or equivalent) - this is the most effective treatment for kidney function recovery 3
• Monitor closely as early identification and treatment may prevent permanent kidney damage, though complete recovery is not guaranteed 5
• Drug reintroduction after nephritis can result in more severe recurrence and should be avoided 3

Critical Pitfalls to Avoid

• Do not attribute hyponatremia to SIADH from malignancy without first excluding pembrolizumab-induced endocrinopathies, as this is a treatable and potentially life-threatening complication requiring specific hormone replacement. 2, 4
• Do not delay corticosteroid therapy while awaiting confirmatory endocrine testing if clinical suspicion for adrenal insufficiency is high, as severe hyponatremia with hypotension can be life-threatening. 4
• Do not assume isolated hyponatremia is benign - it may be the presenting sign of immune-mediated nephritis that requires pembrolizumab discontinuation to prevent permanent renal damage. 5, 3
• Do not restart pembrolizumab after nephritis-related toxicity without careful consideration, as recurrence is typically more severe. 3