Circulating kidney injury molecule-1 (KIM-1) in association with kidney injury biomarkers and outcomes in metastatic renal cell carcinoma

Background: Kidney injury molecule-1 (KIM-1) is overexpressed in clear cell and papillary renal cell carcinoma (RCC) and in proximal tubular kidney injury. While circulating KIM-1 is a minimally invasive biomarker for RCC, it is unknown whether kidney disease, a common comorbidity among RCC patients, impacts the association of KIM-1 with RCC outcomes. We evaluated the association between KIM-1 and outcomes in metastatic RCC after adjustment for multiple kidney injury biomarkers using plasma proteomics. Methods: Plasma samples from patients with metastatic clear cell and papillary RCC were obtained prior to 1st line systemic therapy. Samples were analyzed using a high-throughput aptamer-based proteomics assay (SomaLogic), and results were log-transformed for analysis. Clinical and laboratory data, as well as cancer outcomes, were retrospectively curated. Spearman’s r was used to evaluate correlations between circulating KIM-1 and kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR). Cox regression analyses were used to evaluate the association between KIM1 as a continuous variable and overall survival (OS) and progression-free survival (PFS), after adjusting for kidney injury biomarkers. Performance of KIM-1 tertiles versus IMDC risk groups for prognosticating OS was evaluated using the C-index. Results: Among 210 patients, higher baseline KIM-1 was associated with worse PFS (p = 0.004) and OS (p , 0.001) in univariate Cox regression analysis (Table). The prognostic value of KIM-1 was consistent across clear cell and papillary RCC (p-value for interaction = 0.98). KIM-1 remained prognostic for PFS (p = 0.01) and OS (p , 0.001) after multivariable adjustment for kidney injury biomarkers and eGFR (Table). Median follow-up was 22.1 months. Kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR) were correlated with each other but not with plasma KIM-1. KIM-1 tertiles (high/ medium/low) were more prognostic for OS than the IMDC risk groups (C-index, KIM-1 0.63 vs. IMDC groups 0.58) and the addition of KIM-1 to the IMDC model improved its performance (C-index, KIM-1 + IMDC groups 0.64). Conclusions: Plasma KIM-1 was associated with PFS and OS in metastatic clear cell and papillary RCC. Plasma KIM-1 was not correlated with kidney injury biomarkers, suggesting that at least in metastatic RCC, circulating KIM-1 derives predominantly from tumor rather than benign kidney. The addition of KIM-1 improves IMDC model performance and may be useful for risk prognostication in RCC.