Circulating kidney injury molecule-1 (KIM-1) in association with kidney injury biomarkers and outcomes in metastatic renal cell carcinoma.
Authors: Steiner Clara , Saad Eddy , Saliby Renee Maria , Eid Marc , Semaan Karl , Machaalani Marc , Yekeduz Emre , Horst Jack T. , Lee Jasmine , Phillips Noa , Trowbridge Rachel , Pirovano Marta , Saldanha Neves Horta Lima Carolina , Gupta Shruti , Lee Gwo-Shu Mary , Elon Yehonatan , Dicker Adam P. , Bonventre Joseph , Choueiri Toni K. , Xu Wenxin 
Published: February 2025

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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 1
st
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 ρ 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 KIM-1 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.

Association of KIM-1 with PFS and OS in metastatic RCC. Multivariable models are adjusted for kidney injury markers (cystatin C, TNFR1, TNFR2) and eGFR.

log KIM-1
HR (95% CI)
p-value

OS
(univariate)

1.4 (1.2 – 1.7)
<0.001***

PFS
(univariate)

1.2 (1.1 – 1.4)
0.004**

OS
(multivariate)

1.4 (1.2 – 1.6)
<0.001***

PFS
(multivariate)

1.2 (1.1 – 1.3)
0.01**