How should tyrosine‑kinase inhibitors be managed in patients with impaired renal function?

Management of Tyrosine Kinase Inhibitors in Patients with Impaired Renal Function

TKIs can be safely used in patients with chronic kidney disease and even those on dialysis without routine dose adjustment, though starting at lower doses and titrating upward based on tolerability is recommended for patients with CKD G3a-G5 or on dialysis. 1

Key Management Principles

Dose Adjustment Based on Renal Function

For most multitargeted TKIs (sorafenib, sunitinib, pazopanib, axitinib, cabozantinib, lenvatinib), no mandatory dose reduction is required based solely on renal function. 1 However, the following approach is recommended:

• Start at lower than standard doses in patients with CKD G3a-G5 (eGFR <60 mL/min/1.73 m²) and titrate upward based on tolerability 1
• For dialysis patients, TKIs may be initiated at reduced doses with gradual escalation 1
• Dialysis patients do not require increased frequency of dialysis sessions when receiving TKIs 1

Specific TKI Dosing in Renal Impairment

Imatinib requires specific dose adjustments:

• Moderate renal impairment (CrCl 20-39 mL/min): Reduce starting dose by 50%; maximum dose 400 mg 2
• Mild renal impairment (CrCl 40-59 mL/min): Maximum dose 600 mg 2
• Severe renal impairment (CrCl <20 mL/min): Use with caution; 100 mg/day has been tolerated 2

Critical Monitoring Requirements

Blood pressure normalization at baseline and intensive monitoring during treatment is paramount, as hypertension control is more challenging in patients with impaired kidney function. 1 The monitoring strategy should include:

• Baseline blood pressure optimization before TKI initiation 1
• Frequent blood pressure monitoring throughout treatment, particularly in CKD G3a-G5 1
• Monitor for proteinuria, as TKIs commonly cause this complication 1
• Regular assessment of renal function (serum creatinine and eGFR) 1

Special Considerations for Dialysis Patients

Retrospective data demonstrate that TKIs prolong life expectancy in metastatic renal cell carcinoma even in dialysis patients, with most adverse events being mild in severity. 1 Key management points include:

• Anemia is the most common adverse event in dialysis patients receiving TKIs 1
• Monitor heparin use carefully during dialysis to mitigate bleeding risk 1
• Avoid overhydration, as TKIs have large distribution volumes 1
• No increase in dialysis session frequency is typically required 1

Common Pitfalls and How to Avoid Them

False elevation of serum creatinine can occur with certain TKIs that inhibit MATE-1 (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, tepotinib), mimicking renal injury when true GFR is preserved. 3 To avoid this:

• When creatinine appears elevated on MATE-1 inhibitor TKIs, recalculate GFR using cystatin C before attributing changes to true kidney injury 3
• In 96% of cases, GFR calculated using cystatin C is higher than creatinine-based calculations in patients on MATE-1 inhibitor TKIs 3
• This distinction is critical to avoid unnecessary dose reductions or discontinuation of effective cancer therapy 3

Recognition of True TKI-Induced Nephrotoxicity

TKI-induced renal injury characteristically presents with edema, new-onset or worsened hypertension, and significant proteinuria, with thrombotic microangiopathy (TMA) being the predominant histopathological finding in 80% of biopsy-proven cases. 4 Clinical features include:

• Median time to symptom onset: 9.5 months after TKI initiation 4
• Proteinuria occurs in 95% of cases 4
• Edema in 52% and hypertension in 47% 4
• TMA-like lesions are found in 80% of kidney biopsies 4

Management of Confirmed TKI Nephrotoxicity

When true TKI-induced renal injury is confirmed, prompt discontinuation of the offending TKI coupled with nephroprotective management generally yields favorable outcomes with preservation of kidney function. 4 The treatment approach includes:

• Discontinue the causative TKI immediately 4
• Initiate ACE inhibitor or ARB therapy for nephroprotection 4
• Consider corticosteroids/immunosuppressants in severe cases 4
• Transition to alternative TKI if continued cancer therapy is needed 4
• Complete or partial proteinuria remission occurs in approximately 50% of cases with appropriate management 4

Efficacy in Renal Impairment

Treatment outcomes in patients with renal impairment receiving TKIs are similar to those with normal renal function, with no compromise in cancer control when appropriately managed. 5 Data from dialysis patients show:

• Median progression-free survival: 10.3 months 5
• Median overall survival: 22.6 months 5
• No unexpected adverse events or grade 4 toxicities 5