Nephrotoxicity Associated with Contemporary Renal Cell Carcinoma Regimens: A Systematic Review and Meta-Analysis

Background: The nephrotoxicity profile of contemporary first-line regimens for treatment of metastatic renal cell carcinoma (mRCC) has not been systematically studied in published clinical trials. Objective: To assess the rates of nephrotoxic events of contemporary first-line regimens for treatment of mRCC in comparison to vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) mono-therapy. Methods: We performed a systematic search of the literature looking for randomized clinical trials that contemplated National Comprehensive Cancer Network (NCCN) recommended first-line regimens for treating mRCC in which the control arm was a VEGF-TKI. Selected trials could either include an experimental arm of immune checkpoint inhibitor (ICI) plus VEGF-TKI combination or ICI-ICI combination. Nephrotoxic events were defined as proteinuria, hypertension, blood creatinine increase, acute kidney failure or nephritis, which were all described separately. Results: Five studies satisfied our inclusion criteria. Combination of ICI with VEGF-TKI showed a statistically significant higher degree of proteinuria compared to VEGF-TKI alone. There was no statistically significant difference in rates of hypertension between ICI-TKI and VEGF-TKI alone, but VEGF-TKI alone was statistically significantly more associated with hypertension than immunotherapy alone. Other renal toxicities, such as an increase in creatinine, acute kidney injury (AKI) and nephritis, were uncommon and not consistently reported in each trial. Conclusions: Contemporary regimens for first-line treatment of mRCC are associated with a higher grade of proteinuria than VEGF-TKI alone, while VEGF-TKI is more associated with hypertension than an ICI-ICI combination. Description of many renal toxicities across the studies reported have been diverse and a standardized definition across clinical trials would be helpful to reliably interpret the data regarding nephrotoxicity in the setting of treatment of renal cell carcinoma.