Does belzutifan (Welireg) cause hyperkalemia and acute kidney injury?

Does Belzutifan Cause Hyperkalemia and Acute Kidney Injury?

Yes, belzutifan causes hyperkalemia and acute kidney injury (AKI), though these are not the most prominent adverse effects of this medication.

Evidence from FDA Drug Label and Clinical Trials

Hyperkalemia

Belzutifan does cause hyperkalemia, with increased potassium levels occurring in 29% of patients (2.5% grade 3-4) in the LITESPARK-005 trial for advanced renal cell carcinoma. 1 This represents a clinically significant laboratory abnormality that requires monitoring during treatment.

• In the VHL disease trial (LITESPARK-004), hyperkalemia was not specifically highlighted in the top laboratory abnormalities, suggesting it may be less common or severe in this population 1
• The hyperkalemia appears to be more frequent in patients with advanced RCC who have received multiple prior therapies, likely reflecting the cumulative renal dysfunction from disease and prior treatments 1

Acute Kidney Injury

Belzutifan causes increased creatinine in 64% of patients (0% grade 3-4) in VHL disease and 34% (4.7% grade 3-4) in advanced RCC, indicating renal dysfunction that can manifest as AKI. 1

• The increased creatinine represents on-target effects of HIF-2α inhibition on renal function 2
• Real-world data from Vanderbilt showed that 36.4% of sporadic RCC patients had pre-existing chronic kidney disease, which may predispose them to further renal dysfunction on belzutifan 3
• The mechanism likely involves HIF-2α's role in erythropoiesis and renal oxygen sensing, with inhibition potentially affecting renal hemodynamics 2

Clinical Context and Monitoring

Risk Factors for Hyperkalemia and AKI on Belzutifan

Patients with sporadic RCC are at higher risk than VHL patients due to older age (median 67 vs 41 years), higher rates of chronic kidney disease (36.4% vs 4.5%), and prior nephrectomy (77.3% vs 40.9%). 3

• The combination of pre-existing renal impairment and belzutifan's effects on creatinine creates a vulnerable population 3
• Patients who have received multiple prior lines of therapy (including VEGF inhibitors and checkpoint inhibitors) may have cumulative nephrotoxicity 1

Monitoring Protocol

Check serum creatinine and potassium at baseline and regularly during treatment, with increased frequency in patients with pre-existing renal dysfunction or those on medications that affect potassium homeostasis (ACE inhibitors, ARBs, NSAIDs, potassium-sparing diuretics). 1, 4

• The FDA label recommends monitoring for anemia and hypoxia but does not specify a monitoring schedule for electrolytes and renal function 1
• Given that hyperkalemia occurred in 29% of patients, checking potassium within 1-2 weeks of starting therapy and then monthly is reasonable, with more frequent monitoring if levels are elevated 4, 5
• For patients with eGFR <60 mL/min, monitor creatinine and potassium every 2-4 weeks initially 4

Management of Hyperkalemia on Belzutifan

Mild Hyperkalemia (5.0-5.5 mEq/L)

Review and eliminate contributing medications (NSAIDs, potassium supplements, salt substitutes), optimize diuretic therapy if adequate renal function exists, and increase monitoring frequency to weekly. 5, 6

• Do not discontinue belzutifan for mild hyperkalemia without ECG changes 5
• Consider dietary potassium restriction to <3 g/day, though evidence linking dietary intake to serum levels is limited 5

Moderate Hyperkalemia (5.5-6.0 mEq/L)

Hold or reduce dose of any concurrent RAAS inhibitors by 50%, initiate loop diuretics (furosemide 40-80 mg daily) if eGFR >30 mL/min, and consider dose interruption of belzutifan until potassium <5.5 mEq/L. 5, 6, 1

• The FDA label recommends dose reduction or interruption for adverse reactions, though specific guidance for hyperkalemia is not provided 1
• Consider initiating a potassium binder (patiromer 8.4 g daily or sodium zirconium cyclosilicate 10 g daily) to enable continuation of belzutifan 5
• Recheck potassium within 2-3 days after intervention 6

Severe Hyperkalemia (>6.0 mEq/L) or Any ECG Changes

Discontinue belzutifan immediately, initiate emergency hyperkalemia treatment (calcium gluconate if ECG changes, insulin/glucose, albuterol), and do not restart until potassium <5.0 mEq/L with concurrent potassium binder therapy. 5, 6, 7

• Obtain ECG immediately to assess for peaked T waves, widened QRS, or other conduction abnormalities 5, 7
• Admit to hospital for severe hyperkalemia (>6.0 mEq/L) or any ECG changes 6
• When restarting belzutifan, consider dose reduction from 120 mg to 80 mg or 40 mg daily 1

Management of Acute Kidney Injury on Belzutifan

Monitoring for AKI

Measure serum creatinine at baseline and regularly during treatment, with increased frequency if creatinine rises >0.3 mg/dL from baseline or eGFR decreases by >25%. 4, 1

• AKI is defined by rapid increase in serum creatinine over a short period 4
• Patients with diabetes, heart failure, or pre-existing CKD are at higher risk 4, 3

Management of Increased Creatinine

For creatinine increase <2x baseline without symptoms, continue belzutifan with increased monitoring every 1-2 weeks and optimize volume status. 4, 1

• Ensure adequate hydration and avoid nephrotoxins (NSAIDs, iodinated contrast) 4
• Review concurrent medications that alter renal hemodynamics (diuretics, ACE inhibitors, ARBs) 4

For creatinine increase ≥2x baseline or eGFR <30 mL/min, hold belzutifan until creatinine improves to <1.5x baseline, then restart at reduced dose (80 mg or 40 mg daily). 1

• The FDA label allows dose reduction for adverse reactions, though specific thresholds for renal dysfunction are not provided 1
• Consider nephrology consultation for persistent or severe renal dysfunction 4

Critical Pitfalls to Avoid

Do not ignore mild elevations in creatinine or potassium, as these can progress rapidly in patients with pre-existing renal dysfunction or on multiple nephrotoxic medications. 4, 3

Do not assume that increased creatinine on belzutifan is always drug-related—evaluate for other causes of AKI including volume depletion, obstruction, or progression of underlying malignancy. 4

Do not permanently discontinue belzutifan for moderate hyperkalemia or mild AKI without attempting dose reduction and supportive measures, as this medication provides significant anti-tumor benefit in VHL disease and refractory RCC. 2, 8

Do not delay treatment of severe hyperkalemia (>6.0 mEq/L) or symptomatic AKI while waiting for repeat laboratory confirmation—initiate emergency management based on clinical presentation and ECG findings. 5, 7

Comparison to Other Adverse Effects

While hyperkalemia and AKI do occur with belzutifan, the most prominent adverse effects are anemia (88-93% any grade, 7-29% grade 3-4) and hypoxia (15% in RCC, with 10% grade 3-4), which require more intensive monitoring and management. 1, 3

• Anemia occurs in the majority of patients with median time to onset of 25 days in sporadic RCC and 77 days in VHL 3
• Hypoxia requiring supplemental oxygen occurred in 52.5% of sporadic RCC patients vs 9.5% in VHL patients 3
• Treatment discontinuation due to adverse events occurred in 50% of sporadic RCC patients, primarily driven by anemia and hypoxia rather than hyperkalemia or AKI 3