Biomarkers of Renal Disease

When most laboratory professionals think of tests for renal disease, we think of creatinine and blood urea nitrogen (BUN). These two tests have been considered renal function tests for many years (creatinine for over 100 years), and yet neither is a very good marker of early damage to the kidneys.

Creatinine is a biomarker that really needs individual rather than population-based reference intervals. Each person has a range of creatinine values that are “normal” for them, and that individual range is generally much narrower than the population reference interval. Because the reference interval for creatinine is fairly broad, a person can lose 25 – 50% of their renal function before their creatinine rises out of the reference interval for “normal.” Thus creatinine does not detect early renal damage. BUN is also not great for detecting early acute renal damage. BUN concentrations rise when the kidneys sustain damage, but a rise in BUN is not specific to kidney damage. Other causes can elevate BUN as well, such as starvation and increased protein breakdown or intake. In general, BUN and creatinine provide the most useful information in conjunction with each other, and for trending when significant damage to the kidneys has already occurred.

For these reasons, there is a continuous search for better markers of renal damage, especially markers that indicate early renal damage, when perhaps something can be done to reverse it. Cystatin C is another biomarker that is being increasingly used to assess renal damage, and originally was hoped might outperform creatinine in detecting early renal damage. Cystatin C is a small protein which is freely filtered by the glomerulus and doesn’t have many of the drawbacks of creatinine, such as creatinine’s relationship to muscle mass. Unfortunately, although many studies have been done, cystatin C has not been shown to be better than creatinine at indicating early renal damage, and is considered a renal biomarker with uses similar to creatinine and BUN.

Currently, protein or albumin in the urine, and especially very small amounts of protein/albumin in the urine, is probably the earliest indicator of renal damage that is available in the US. Very small amounts of albumin in the urine, what has been called microalbuminuria, is one of the earliest indicators of renal disease.

A new biomarker for early acute renal damage that is gaining the most widespread acceptance is NGAL. Neutrophil gelatinase-associated lipocalin (NGAL) is being extensively studied and has been shown to detect early, acute kidney injury (AKI). In addition, NGAL levels have been reported to be associated with the amount and severity of renal damage. Already in use clinically in Europe, tests for this biomarker are currently working their way through the FDA in the US.

Some other new biomarkers for AKI that are being studied, but are not progressing toward general usage as quickly as NGAL include kidney injury molecule 1 (KIM-1), β-trace protein, liver-type fatty acid-binding protein (L-FABP) and interleukin-18. These are all proteins that appear to be up-regulated in response to AKI. Studies are on-going to see which of these biomarkers may be useful for detecting early AKI and for differentiating between types and causes of AKI. In addition, for all these new kidney biomarkers, studies are needed on the biomarkers’ efficacy in helping with clinical decision-making regarding treatment options and outcomes. It will be interesting to see if any of them become clinically useful tests for the detection of early acute renal damage.

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

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