Immune checkpoint inhibitors further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy

Abstract

Background: Increasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosinekinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria's and renal function's condition since the administration of PD-1 inhibitor.Methods: To assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%).Results: Of the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m 2 to 66.75 mL/min/1.73 m 2 after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent's survival (P<0.001).Conclusions: Targeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.

Comparison of different estimated glomerular filtration rates for monitoring of kidney function in oncology patients

“…In our study, we have also noticed an increase in proteinuria, namely a 50% increase in UPCR, compared to baseline, throughout treatment, with 57% of patients having mild to severe proteinuria. This finding of TKI-related proteinuria is in line with recent reports [ 32 , 33 ], including a meta-analysis from Xiong et al . [ 33 ] highlighting the risk of renal impairment by the administration of TKIs [ 33 ].…”

Development and validation of a novel defined mutation classifier based on Lasso logistic regression for predicting the overall survival of immune checkpoint inhibitor therapy in renal cell carcinoma

“…More accurate methods, such as spatial transcriptome sequencing, can be used to further confirm the immune infiltration status in RCC. Third, clinicopathological characteristics such as exacerbation in proteinuria after ICI therapy (52), may also influence the prognosis of RCC patients, more adverse events post ICI treatment should be considered in future studies. Fourth, the mechanisms to stratify advanced patients with RCC into groups with different OS times underlying the 10-gene mutation classifier remain unclear.…”

Prevalence and management of proteinuria associated with vascular endothelial growth factor receptor‐targeted tyrosine kinase inhibitor treatment in advanced renal cell carcinoma, hepatocellular carcinoma, and thyroid cancer

“…The current primary treatment for mRCC is the combination of VEGFR‐TKIs and ICIs. There are reports showing that prolonged TKI administration and PD‐1 inhibitors are predictors of proteinuria development, and that prolonged TKI administration is a prognostic predictor of decreased renal function 60 . Moreover, the combination of an ICI and VEGFR inhibitor compared with sunitinib alone increased the risk of proteinuria development 61,62 .…”

“…There are reports showing that prolonged TKI administration and PD-1 inhibitors are predictors of proteinuria development, and that prolonged TKI administration is a prognostic predictor of decreased renal function. 60 Moreover, the combination of an ICI and VEGFR inhibitor compared with sunitinib alone increased the risk of proteinuria development. 61,62 Therefore, the occurrence of proteinuria may be due to a direct effect of concomitant use of an ICI with a VEGFR inhibitor, or an indirect effect of a prolonged duration of TKI administration.…”