Does Venetoclax (Venetoclax) commonly cause Acute Kidney Injury (AKI)?

Venetoclax and Acute Kidney Injury Risk

Venetoclax does not commonly cause acute kidney injury (AKI) directly, but it can indirectly lead to AKI through tumor lysis syndrome (TLS), which requires appropriate prophylaxis and monitoring.

Mechanism of Potential Kidney Injury

• Venetoclax itself is not directly nephrotoxic, but it can cause rapid tumor cell death leading to tumor lysis syndrome (TLS), which may result in acute kidney injury 1
• TLS occurs due to rapid release of intracellular contents (potassium, phosphorus, nucleic acids) when cancer cells are destroyed, potentially causing electrolyte abnormalities and acute kidney injury 2
• Pharmacokinetic studies show venetoclax undergoes primary metabolism and clearance in the liver with minimal renal excretion, suggesting limited direct nephrotoxicity 3
• Even in patients with end-stage renal disease on hemodialysis, venetoclax pharmacokinetics are not significantly altered, further supporting its minimal direct renal effects 4

Incidence of Kidney Injury with Venetoclax

• In a real-world study of 106 patients receiving venetoclax with hypomethylating agents, 5% developed clinical TLS with acute kidney injury 2
• The median time to develop TLS was 2 days (range -2 to 4) after initiation of therapy 2
• Compared to other causes of drug-induced AKI, venetoclax-associated AKI through TLS is less common than nephrotoxicity from agents like vancomycin 5

Risk Factors for Venetoclax-Associated Kidney Injury

• High tumor burden, particularly in CLL patients, increases TLS risk 1
• Impaired baseline renal function (CrCl <80 mL/min) is a significant risk factor 1
• Concomitant use of strong CYP3A4 inhibitors (like azole antifungals) increases venetoclax exposure and potentially TLS risk 1
• Inadequate hydration before and during treatment initiation 1

Prevention Strategies

• Gradual dose ramp-up is essential - for CLL, start at 20 mg and gradually increase to target dose (400 mg) over 5 weeks 1
• Aggressive hydration is critical - oral hydration (1.5-2L daily) plus intravenous hydration as needed 1
• Prophylactic allopurinol or other uric acid-lowering agents should be started 2-3 days prior to venetoclax initiation 1
• Consider hospitalization for patients with CrCl <80 mL/min during initial dosing (20 mg and 50 mg) 1
• Regular monitoring of blood chemistries (potassium, uric acid, phosphorus, calcium, and creatinine) at pre-dose, 6-8 hours, and 24 hours during dose ramp-up 1
• For patients receiving venetoclax with azole antifungals, reduce venetoclax dose by 75% to prevent excessive drug exposure 1

Management Recommendations

• For patients at high risk of TLS, consider inpatient treatment during dose escalation with more intensive monitoring 1
• If TLS develops, temporarily hold venetoclax and manage electrolyte abnormalities aggressively 1
• Consider dose interruptions to allow for hematologic recovery in patients with good response but persistent cytopenias 1
• In patients with AML receiving venetoclax with hypomethylating agents, close monitoring during the first 7-10 days of treatment is crucial 2

Special Considerations

• Venetoclax can be safely used in patients with renal impairment, including those on hemodialysis, without dose adjustment based on renal function alone 4
• Patients with CLL may have underlying renal involvement from their disease, which could increase the risk of AKI during treatment 6
• When using venetoclax in combination with other potentially nephrotoxic agents, increased vigilance for AKI is warranted 5