Plasma KIM-1 as a Preoperative Biomarker for RCC

Wenxin Xu, MD, of Dana-Farber Cancer Institute, and Daniel Joyce, MD, of Vanderbilt University Medical Center, explain the rationale behind recent research on plasma kidney injury molecule-1 (KIM-1), the significance of KIM-1 as a biomarker, and its potential to revolutionize the diagnosis and treatment of kidney cancer.

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Dr. Joyce: Talk to me a little bit about what was your rationale for pursuing this study? What was the question you were trying to answer, and how did you come up with it?

Dr. Xu: The background for KIM-1 is that it is a biomarker detectable in the blood and has been investigated for kidney cancer by multiple groups, including ours, in the past. The biomarker itself is a transmembrane protein found on the cell membrane and is cleaved off by metalloproteinases. It has a domain that circulates in the plasma or serum and can be detected by various assays. There is substantial prior data showing that in patients with kidney cancer, KIM-1 is elevated in the plasma and can be detected as a biomarker, similar to how we use other tumor markers like PSA or CA125.

In the kidney cancer clinical area specifically, there is a dilemma for many patients who have a renal mass, where it is uncertain if the mass is benign or malignant. Kidney biopsies in these situations are not always reliable because of the potential for false negatives.

What we find is that in large cohorts, there is consistently a significant proportion of patients—around 25%—who undergo partial nephrectomy and end up having a benign mass. We aim to avoid this unnecessary surgery.

In this paper, we look at KIM-1 as a way to risk stratify masses: are they likely malignant, benign, or indolent? This helps identify patients who would benefit most from surgery.

Dr. Joyce: KIM-1, just for clarity, is this something that we find in all kidney cells, or is it specific to kidney cancer cells or kidney cells undergoing injury?

Dr. Xu: Yes, the name is descriptive—kidney injury molecule-1. In healthy individuals, KIM-1 is not elevated and is not normally expressed in the kidney. However, it is overexpressed when the kidney undergoes hypoxic injury.

The first papers on KIM-1 described it in patients undergoing cardiac surgery with cardiopulmonary bypass and kidney hypoxia. We see that in patients with kidney cancer, many of these same hypoxic pathways are upregulated, leading to KIM-1 overexpression. This led to its use as a biomarker, specifically in kidney cancer. It is interesting because it is a kidney tubular epithelial protein and is elevated in both clear cell and papillary kidney cancer.

Dr. Joyce: That is really exciting. It is potentially the first marker for papillary kidney cancer that we have seen, which is great.

You have looked at 2 different cohorts, 1 in Russia and 1 at Johns Hopkins. You have examined a wide variety of sizes, with the Hopkins cohort having smaller renal masses and the Moscow cohort having a greater variety, including larger masses. Tell us, what did you find with KIM-1? What is its significance, and what are the takeaways from the study?

Dr. Xu: One of the exciting findings from this study is that plasma KIM-1 is elevated in patients with both large and small renal masses. It is one of the first minimally invasive circulating biomarkers elevated even in pT1a (4 centimeter) renal masses. We do see that the elevation is greater in larger masses, which is consistent across all circulating biomarkers; the larger the tumor, the more material it sheds into the circulation. Prior studies show that the more tumor present, the higher the KIM-1 levels. For example, in metastatic settings, patients with metastatic RCC have KIM-1 levels several orders of magnitude higher than what we saw here.

Dr. Joyce: Interesting. For these oncocytomas that we might follow in patients we do not want to operate on, is KIM-1 more helpful with larger oncocytomas than with smaller 3-centimeter masses?

Dr. Xu: It could be helpful if you are differentiating between an oncocytoma and a more aggressive malignant mass. We do not have KIM-1 production by oncocytomas because they have a different cell origin compared to clear cell or papillary renal tumors. So KIM-1 is helpful if the differential diagnosis is between an oncocytoma and, for example, papillary kidney cancer.

Dr. Joyce: I know you did not look at this, but do you see potential in combining this liquid biopsy with new imaging techniques like CA9 or sestamibi? Could there be added benefit from these combinations?

Dr. Xu: That is an important question. Carbonic anhydrase IX-girentuximab-based PET imaging presented at ASCO GU 2024 showed exciting data with sensitivity and specificity for detecting clear cell kidney cancer. Biologically, you would expect these assays to have additive predictive capacity. If a mass lights up on PET and expresses KIM-1, it is probably highly likely to be a clear cell renal cell carcinoma.

Dr. Joyce: One limitation you mentioned is that KIM-1 is elevated in patients with kidney injury from other causes besides cancer. Often, these patients we discuss for active surveillance versus operative intervention have CKD and other issues that make us hesitant to proceed with treatment. How would you view this marker in these patients, and could future work differentiate levels based on pre-existing kidney injury?

Dr. Xu: I agree. KIM-1 is elevated in CKD and AKI, but it is important to understand the degree of elevation. In patients with confirmed clear cell RCC, KIM-1 levels do not correlate with creatinine because the tumor-produced KIM-1 overwhelms the normal kidney’s production. It is a different order of magnitude. However, in patients without kidney cancer, KIM-1 levels do correlate with ongoing kidney hypoxic injury.

Future approaches might measure multiple kidney injury biomarkers, such as cystatin C, creatinine, and KIM-1, to help differentiate whether KIM-1 is coming from hypoxic kidney or a small tumor.

Dr. Joyce: Fantastic. It is really exciting to have some signal from a liquid biopsy to help guide treatment in this challenging clinical situation. We are still over-treating these masses a lot, and it is nice to see new technology on the horizon that might help. Where are you going next with this work, and what are the next steps?

Dr. Xu: It is exciting to see emerging data on KIM-1 not just from retrospective studies, but also from prospective and randomized adjuvant trials. Data on KIM-1 has been presented for the ASSURE adjuvant trial in RCC and more recently for the CheckMate 914 adjuvant trial. In a couple of days, we will see data at ASCO on KIM-1 in IMmotion010, the adjuvant atezolizumab trial. These trials show that KIM-1 is prognostic, and in some immunotherapy trials, KIM-1 is predictive for adjuvant immunotherapy benefit.

This field is promising because we know adjuvant immunotherapy with pembrolizumab has disease-free and overall survival benefits. However, many patients are over-treated; over half would not have had a recurrence without the pembrolizumab. This is a ripe opportunity to better select patients. We can identify those who do not need adjuvant therapy and perhaps find those who are not eligible based on clinical criteria but have high KIM-1 and might benefit.