Retrospective Cohort Study Evaluating the Association Between Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use and Tyrosine Kinase Inhibitor-Associated Toxicity in Advanced Renal Cell Carcinoma

Purpose: Tyrosine kinase inhibitors (TKIs) used to treat advanced renal cell carcinoma are associated with clinically significant toxicities, including hypertension and acute kidney injury. Because angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEis/ARBs) have established antihypertensive and renoprotective effects, they may be associated with lower rates of TKI-related toxicity. This study evaluated the association between ACEi/ARB use and TKI-associated toxicity.Materials and Methods: We conducted a retrospective observational cohort study using data from the United States TriNetX research network and Penn State Hershey Medical Center (HMC). Patients receiving TKI therapy were stratified according to concurrent ACEi/ARB use. Primary endpoints included kidney function parameters (urine protein, blood urea nitrogen [BUN], and creatinine) and blood pressure measurements. Secondary outcomes included TKI dose discontinuation events. Group comparisons were performed using the Wilcoxon rank-sum test for continuous variables and Fisher exact test for categorical outcomes.Results: In the combined TriNetX and HMC cohorts, ACEi/ARB use was associated with a statistically significant reduction in documented proteinuria diagnoses (absolute reduction, 19.1%; p=0.036). No significant differences were observed in BUN levels or systolic or diastolic blood pressure. In the HMC cohort, ACEi/ARB use was associated with lower creatinine levels at 4–6 weeks after ACEi/ARB initiation (mean reduction, -0.4 mg/dL; p=0.050) and a 13.7% absolute reduction in TKI discontinuation events. Because of the retrospective observational design and absence of adjustment for baseline confounders, these findings should be interpreted as associative.Conclusion: ACEi/ARB use was associated with lower rates of proteinuria, possible improvement in creatinine levels, and fewer treatment discontinuation events. These findings suggest that ACEis/ARBs may help reduce selected TKI-related toxicities. Prospective studies are needed to clarify dose-dependent and temporal effects in patients with renal or vascular comorbidities.