Urinary Biomarkers for Renal Cell Carcinoma

 

Introduction

Renal cell carcinoma is the most common kidney cancer, often found by chance during imaging for other issues. A significant problem we face is that imaging alone cannot always tell if a small kidney mass is benign or cancerous. This leads to surgeries that later turn out to be unnecessary for about 20-30% of patients. Urine tests offer a non-invasive way to find biomarkers that could help make this distinction before surgery, but none are used in the clinic yet.

Important Concepts

Renal Cell Carcinoma (RCC): The main type of kidney cancer, making up 90% of cases. Its common subtypes are clear cell, papillary, and chromophobe.

Urinary Biomarker: A measurable substance in urine that can indicate the presence or status of a disease, like cancer.

Diagnostic Panel: A combination of several biomarkers tested together, which often performs better than a single marker alone.

Liquid Biopsy: A test done on a body fluid, like urine, to find disease. It is simpler and less invasive than a tissue biopsy.

What We Know

Promising Biomarker Categories

• A total of 105 individual urinary biomarkers were identified, falling into several types.
• These include metabolites, proteins, microRNAs (miRNAs), and DNA methylation markers.
• Additionally, 29 different multi-biomarker panels were described.
• Combining biomarkers into panels generally improves diagnostic accuracy over single markers.
• Only a few markers, like AQP1, PLIN2, and miR-122-5p, have been studied in more than one research paper.

Reported Diagnostic Performance

•  Promising individual metabolites include D-sedoheptulose-7-phosphate and N-jasmonoyltyrosine.
• The proteins AQP1 and PLIN2 showed excellent results in some studies, with AUCs up to 1.00.
• miRNAs such as miR-15a and miR-30c-5p demonstrated high diagnostic potential.
• A miRNA-based panel called the 7p-urinary score showed good performance in initial and validation studies.
• Panels based on volatile organic compounds and phosphoproteins also showed high AUCs.

Challenges for Clinical Use

• A major limitation is the lack of external validation in different patient groups for most markers.
• Study sizes are often small, which can overestimate how well a biomarker works.
• Factors like diet, urine collection time, and different lab techniques make results hard to compare.
• The origin of a urinary biomarker is not always specific to kidney cancer.
• There is no standard way to normalize measurements for things like urine concentration across studies.

Important Numbers

• 20–30%: The proportion of small renal masses surgically removed that are later found to be benign. This highlights the need for better pre-operative diagnosis.

• AUC ≥ 0.80: The performance threshold for a promising diagnostic biomarker. Values below this have limited clinical utility on their own.

• 100% Sensitivity & Specificity: Reported in some studies for proteins AQP1 and PLIN2, indicating perfect separation between patients and controls in those particular cohorts.

• 46 studies:  The number of good quality studies in this field, showing the volume of research in this area.

• 105 individual biomarkers:  The total number of distinct urinary biomarkers identified for RCC detection.

• 8.7%: The small percentage of studies that had a sample size of over 100 patients, indicating a need for larger studies.

The Urologist's Summary

1. Initial Imaging & Clinical Suspicion: A renal mass is identified incidentally via ultrasound, CT, or MRI. The diagnostic challenge, especially for small masses (≤4 cm), is determining its malignant potential.
2. Biomarker Investigation (Research Context):  In a research setting, a urine sample is collected. The focus is on analyzing specific biomarkers or panels, such as AQP1/PLIN2 proteins, certain miRNAs (e.g., miR-122-5p), or metabolite panels that show high diagnostic accuracy (AUC ≥ 0.80).
3. Integration & Future Application: The results from the urinary biomarker analysis are combined with imaging findings. The goal is to improve the pre-operative distinction between benign lesions and RCC, thereby helping to avoid unnecessary nephrectomies. This step requires extensive validation before clinical use.

The Point

Urinary biomarkers show real potential for a non-invasive and accurate diagnosis of renal cell carcinoma. However, robust external validation and standardization are urgently needed before they can become a tool in our everyday clinical practice.

For further data about urologic diseases diagnosis and therapeutic options, follow our blog 

The Urologist

By:

Dr. Ahmed M. Bakr, MD, FEBU

Reference: Kelly et al. BMC Cancer (2025) 25:1672. https://doi.org/10.1186/s12885-025-14900-8