KIM‐1: From Prognostic Indicator to Therapeutic Stratification Tool in Adjuvant Renal Cell Carcinoma

We read with interest the article by Sugai et al. [1] focusing on the tissue expression of Kidney injury molecule-1 (KIM-1) in clear cell renal cell carcinoma (RCC) as a potential biomarker for the risk of recurrence after radical surgery. A paramount challenge in contemporary urological oncology is to identify the subset of post-nephrectomy patients requiring adjuvant immunotherapy in RCC to reduce the risk of both overtreatment and undertreatment. In this context, recent clinical trial data have highlighted circulating KIM-1 as a promising biomarker candidate for postoperative risk stratification. Sugai et al. provide timely biological context by linking tumor KIM-1 expression with features of the tumor immune microenvironment, and their recurrence-free survival (RFS) findings are directionally consistent with clinical-trial observations based on circulating KIM-1. While the role of KIM-1 as a prognostic biomarker has been reassured in the ASSURE trial, post-hoc analysis of data from the CheckMate 914 and IMmotion010 trials indicate a more nuanced role where subgroups of patients with high baseline KIM-1 post-operative levels were associated with the worst prognosis indicating high-risk of relapse as observed with inferior disease-free survival (DFS) and a high risk of relapse [2-5]. In CheckMate 914 and IMmotion010, adjuvant nivolumab plus ipilimumab or atezolizumab, respectively, showed a numerically greater DFS benefit versus placebo in the KIM-1 high subgroups than in the overall ITT populations (Figure 1) [4, 5]. This suggests that elevated KIM-1 levels post-nephrectomy indicate the presence of active, immunogenic, microscopic residual disease. Thus, it could act as a dynamic marker of therapeutic vulnerability, indicating the necessity for trialing with immune checkpoint inhibitors (ICIs). Nevertheless, KIM-1 has not been integrated into clinical therapeutic decision-making, primarily due to the lack of high-quality trials validating its predictive role. Another challenge is that the threshold cut-off values for KIM-1 have not been established across the populations. This has prevented its adoption in clinical practice and standard treatment guidelines. Also, variations in the assays used to estimate KIM-1 levels pose challenges. In order to translate promising post-hoc signals into real-life clinical utility, future adjuvant ICI trials in RCC should pre-specify KIM-1 as a biomarker strategy. These trials should implement standardized and widely reproducible assays across matrices and modalities (tumor tissue expression and circulating KIM-1, with urine as a complementary non-invasive matrix), establish clinically meaningful thresholds that enable patient stratification, and directly compare these approaches to determine the most informative and feasible method for clinical decision-making. In the era of biomarker-guided therapy, convergent evidence from tumor tissue biology and circulating measurements makes KIM-1 an attractive candidate. The next step is prospective validation using standardized assays and pre-defined cut-offs, followed by biomarker-stratified trial designs to determine whether KIM-1 can reliably guide postoperative adjuvant ICI decisions in high-risk RCC. Kannan Sridharan: conceptualization, writing – original draft preparation. Ondrej Fiala: writing – review and editing, supervision. Matteo Santoni: writing – review and editing, supervision. All authors approved the final version of the manuscript. Ondrej Fiala received honoraria from Novartis, Janssen, Merck, Ipsen, BMS, MSD, Pierre Fabre, and Pfizer for consultations and lectures unrelated to this work. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas and Bayer, all unrelated to this work. Kannan Sridharan has no conflict of interest.