In October’s Clinical Laboratory News, Joe M. El-Khoury, PhD, DABCC, FAACC, explores the current limitations of measuring kidney function and why one emerging endogenous biomarker may serve as an ideal candidate for diagnosing chronic kidney disease (CKD), paving the way for a faster, more automated test down the road.
Glomerular filtration rate (GFR), determined by measuring the clearance of a substance from blood into urine, is the most reliable index for measuring kidney function. But to truly reflect GFR, this substance must meet at least five criteria, explains El-Khoury, an assistant professor of laboratory medicine at Yale University School of Medicine and co-director of the clinical chemistry laboratory and clinical chemistry fellowship program at Yale-New Haven Health.
“To date, no single known biomarker produced by the human body meets all these characteristics. As a result, laboratories use clearance of exogenous markers such as iothalamate and iohexol as a reference method for determining GFR, while using serum measurement of endogenous markers such as creatinine and cystatin C for estimating GFR (eGFR),” he writes.
Using exogenous markers is costly and invasive, however, making it an impractical screening alternative. Serum creatinine to measure for kidney disease has other problems. Creatinine is the waste product of interconversion between phosphocreatine and creatine in muscle cells, and a number of variables can affect its production levels such as muscle mass, age, sex, and race. Equations developed to address these variations have improved accuracy but don’t account for diet, medications, and other factors that affect creatinine. Cystatin C in the meantime has proven to be a stronger marker of kidney function than creatinine but is more expensive and is also affected by nonrenal factors such as thyroid function, obesity, and inflammation, El-Khoury summarizes.
Already widely used in veterinary medicine, symmetric dimethylarginine (SDMA) has emerged as a biomarker of interest in clinical research. “Asymmetric dimethylarginine (ADMA) and SDMA both are produced consistently by hydrolysis of histones with post-translational methylation of arginine residues. In addition, SDMA is almost exclusively eliminated by the kidneys after filtration, making it an ideal candidate for a GFR marker,” according to El-Khoury.
A number of studies have shown a highly significant correlation between SDMA and kidney function. SDMA also seems more durable than creatinine and/or cystatin C in that nonrenal factors and conditions such as diabetes, cardiovascular disease, hepatic disease, or acute inflammatory response don’t seem to affect its concentration. El-Khoury notes that “SDMA levels have been shown to be slightly increased based on age and sex, so it is likely that a GFR estimating equation using SDMA would need to take at least these two variables into account.”
His own group in 2016 published the first report that compared SDMA’s performance with creatinine and cystatin C in measuring GFR. “Although the sample size was small (n=40), SDMA showed similar correlation with GFR as reported in larger studies,” he reports. In one study of a pediatric population, SDMA performed better than cystatin C in identifying early stage CKD. Another significant advantage of SDMA is its early rise during CKD’s pathological process.
SDMA measurement to date has mostly taken place in translational research laboratories with liquid chromatography tandem mass spectrometry (LC-MS/MS) instruments. “While the adoption of LC-MS/MS by clinical laboratories has increased in recent years, the technology remains complex and requires a significant level of expertise for test development and operation,” El-Khoury writes. LC-MS/MS assays for SDMA aren’t fully automated and have less than ideal turnaround time (TAT) in comparison to creatinine and cystatin C assays.
An automated, pre-commercial immunoassay for SDMA performed well in comparison to LC-MS/MS in one study, raising hope that this biomarker may someday be used in clinical practice.
Pick up October’s CLN to learn more about future applications of SDMA in identifying CKD.