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.

No abstract

Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value.