The Value of Urinary Biomarkers in the Setting of Renal Dysfunction

05/05/25

Understanding the Value of Urinary Biomarkers in the Setting of Renal DysfunctionEarly identification of kidney dysfunction is critical to prompt intervention and improved patient outcomes. While serum creatinine (SCr) and urinary output (UO) serve as two important measures, urinary biomarkers represent yet another emerging key tool in the efforts to recognize reduced kidney performance sooner and monitor subsequent therapeutic response to treatment.

In general terms, biomarkers, as defined by the World Health Organization (WHO), are “any substance, structure or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease.” 1 Urinary biomarkers can include proteins, urinary metabolites, genetic material, electrolytes, and urinary extracellular vesicles (uEVs).2

Because they originate from almost all cell types throughout the kidneys and other urinary tract tissues and serve as a carrier of information both within and between cells, uEVs represent a potent source of molecular biomarkers to help identify physiological and pathological conditions. 3

By analyzing urine samples for available biomarkers, clinicians can receive in-depth feedback on the current state of kidney function as well as root causes of any identified problems.

The Basics: Kidneys and Their Function

The essential role of the kidneys in filtering waste products from the body is an important concern and one that healthcare providers remain keenly aware of. These dual organs filter an average of 180 liters of blood each day in healthy individuals and are also responsible for helping with the regulation of electrolytes, maintaining acid-base balance, and producing hormones that help regulate blood pressure and red blood cell production.

The small filtering units of the kidneys, the nephrons, are made up of both a small renal tubule and small blood capillaries, including a specific capillary structure called the glomerulus. These delicate structures are susceptible to damage and/or injury in several common ways. This includes kidney stones, infections, autoimmune-mediated inflammation (glomerulonephritis), hereditary kidney disease (polycystic kidney disease), chronic kidney disease (most often due to diabetes or high blood pressure), and acute kidney injury (AKI).

The Value of Urinary Biomarkers

Urinary biomarkers can identify a range of diseases and provide a detailed evaluation of systemic conditions as well as kidney function. To date, thousands of urinary biomarkers have been identified, and aid in (or demonstrate potential to aid in) the detection of cancers, neurodegenerative disease, infection, inflammatory and autoimmune conditions, chronic kidney disease, and AKI, among other conditions. 4

Part of the value of urinary biomarkers is due to their discrete sensitivity to many factors, such as age, gender, diet, and more. For example, systemic oxidative stress can be evaluated using urinary biomarkers, offering a potential approach to identifying those at increased risk for developing age-related diseases. 5

It is this level of sensitivity that makes urinary biomarkers especially useful for identifying AKI earlier than is possible with serum creatinine values. 6 Together with other early indicators of renal dysfunction, such as real-time, automated urine output monitoring, it is easier to intervene before ongoing damage escalates to acute renal failure and increased risk of mortality and morbidity.

Classification of Biomarker Families

Several specific biomarkers have been identified and can be classified in relation to kidney function. These include markers of kidney injury, markers of glomerular function, markers of tubular dysfunction, markers of inflammation and immune response, and markers of cell cycle regulation and stress.

The differences in these biomarkers and what they are capable of identifying illustrates that no single biomarker provides the complete picture of renal status. However, used in combination, they have the potential to provide valuable clinical guidance to identify kidney injury.

Thus far, a few specific biomarkers have been identified as especially useful in the early identification of AKI. Here, we discuss three important urinary biomarkers that hold significant promise:

NGAL

Neutrophil gelatinase-associated lipocalin (NGAL) is an antibacterial protein which serves as a marker of kidney injury and is highly specific for early identification of AKI. It is produced by several types of cells in the body, including neutrophils, and cells in the digestive and respiratory systems. Importantly, it is also produced by the kidney tubule in response to damage, likely as a protective measure. 7

NGAL levels rise rapidly in response to injury to the kidney, well ahead of a rise in serum creatinine. Studies illustrate that this effect can be detected days ahead of any significant rise in creatinine, which must be increased by at least 50% to meet RIFLE criteria for AKI. 8

In addition to supporting early detection and prompt intervention in response to AKI, evidence also shows that NGAL is accurate in predicting risk of morbidity and mortality. For example, in patients with AKI who require renal replacement therapy (RRT), NGAL levels were found to correctly predict 28-day mortality. 9

However, one significant drawback of NGAL is its lack of specificity for solely renal impairments. Some studies have indicated variability in results between patients, with NGAL also reflecting conditions such as sepsis, cancer, and inflammation, limiting its accuracy as a positive indicator of renal damage.10

In the case of infection and especially sepsis vs. renal dysfunction, it is crucial to differentiate between root causes of elevated NGAL early in the clinical course. Ultimately, NGAL holds value as a potential tool to aid in quickly and accurately understanding a patient’s condition and overall risk and can help guide treatment decisions early in their clinical course, with a goal of improving outcomes.

KIM-1

Kidney injury molecule-1, or KIM-1, is a biomarker that has been recognized as a sensitive indicator of kidney injury. In particular, studies suggest that it has both high specificity and sensitivity. 11 Resulting from tubular injury, KIM-1 is undetectable in healthy kidneys but rises in response to acute kidney injury.

To date, the use of KIM-1 has been approved by the U.S. Food and Drug Administration (FDA) as a tool to identify drug-induced AKI in preclinical trials. 12 Research has continued to refine the use of KIM-1 in clinical settings, including the ability to return rapid results on testing. 13

While KIM-1 has shown great promise, it still demonstrates weak ability to predict AKI or even distinguish between AKI and non-AKI patients early in the clinical course, limiting its ability to stand alone as an independent biomarker. This is because significantly elevated KIM-1 levels may not be present until the advanced stages of kidney injury, compromising clinicians’ ability to quickly identify and treat dysfunction earlier based soley on KIM-1. 14

Cystatin C

Another urinary marker of kidney injury, cystatin C is produced by nucleated cells in the body, filtered by the glomeruli, and rises in response to kidney injury. In a healthy individual, this protein would normally be reabsorbed by the renal tubules and is not present in urine in any significant amount, but in cases of kidney dysfunction, is excreted in urine in increasing amounts. 15 It has been shown to be an effective biomarker for predicting AKI, AKI severity, sepsis, and mortality. 16

One specific use suggested for cystatin C is in identifying patients at risk for AKI following cardiothoracic surgery. Over 40% of patients undergoing cardiothoracic surgery develop AKI, making early detection in this population critical. 17 Cystatin C, along with NGAL, have been investigated as early predictors of this complication; cystatin C levels 6 hours after ICU admission are shown to most useful in predicting injury. 18

This biomarker, like others, serves as an earlier predictor of AKI than standard measures such as creatinine. Cystatin C is preferred over creatinine as it is unaffected by age, muscle mass, or diet, and is a more reliable glomerular filtration rate (GFR) marker, especially in early renal impairment when creatinine levels are normal. It is also used in eGFR equations like the combined creatinine-cystatin KDIGO CKD-EPI equation. 19

While cystatin C’s characteristics well overcome those of more conventional biomarkers like serum creatinine, cost and availability continue to be barriers in widespread adoption of these tests. Reagent cost is many times that of SCr ($5-$10 per test vs. $0.50), and one survey indicated that only 7% of U.S. clinical laboratories perform cystatin C testing, requiring more than 90% of these tests to be sent to commercial laboratories. Additionally, there exists concerning variability between assay performance across facilities. 20

Future Research Directions

Current guidelines are still being developed to enhance the understanding of early predictive biomarkers of acute kidney injury. Some studies have shown both disadvantages and limitations with some of the currently identified urinary biomarkers, including lack of adequate sensitivity and specificity. 21 Additionally, they are not yet widely available and are more expensive than other more common tests.

However, urinary biomarkers remain a promising approach to identifying AKI earlier than is possible with current standardized tools such as RIFLE, KDIGO, serum creatinine, and GFR.

Additionally, intensive urine output (UO) monitoring shows important value in cost-effective, early identification of AKI. For example, one study found that intensive UO monitoring significantly improved 30-day survival compared to less intensive monitoring. 22

Similar to use of urinary biomarkers, careful and precise UO monitoring allows clinicians to detect small changes in kidney function ahead of a rise in SCr. In particular, automated urine monitoring has been shown to be more accurate, timely, and associated with better outcomes. 23

As the use of urinary biomarkers advances, their potential — in combination with precision urine output monitoring — represents meaningful advancements from current algorithms for identifying and managing acute kidney injury and acute kidney failure.

References

The Value of Urinary Biomarkers in the Setting of Renal Dysfunction

05/05/25

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