Blood creatinine levels may best mark progression, therapy response
Study sees potential for byproduct of muscle function to be sensitive biomarker
Blood levels of creatinine, a byproduct of normal muscle function, may be a potential biomarker of disease severity and treatment response in adults and adolescents with spinal muscular atrophy (SMA), a study in China shows.
Creatinine levels, overall, strongly associated with disease severity across two years of follow-up, and they predicted changes with treatment in a patient’s motor abilities with greater accuracy than other, commonly used biomarkers, the researchers wrote.
The study, “A cross-sectional and longitudinal evaluation of serum creatinine as a biomarker in spinal muscular atrophy,” was published in the Orphanet Journal of Rare Diseases.
More sensitive and reliable biomarkers needed to track disease in people
SMA is chiefly caused by mutations in the SMN1 gene, which result in a deficiency of the SMN protein. The loss of this protein particularly affects motor neurons — the nerve cells that control voluntary movements — leads to hallmark disease symptoms like muscle weakness and wasting.
Given the arrival of disease-modifying therapies that work to increase SMN protein levels, and patients’ varying responses to these treatments, “it is imperative to identify biomarkers demonstrating high sensitivity, reliability, and accessibility for monitoring treatment efficacy and disease progression,” the researchers wrote.
Current SMA biomarkers, which can range from SMN and neurofilament protein levels to imaging markers like MRI and muscle ultrasound, can lack the needed sensitivity and accuracy, the researchers noted. Creatinine, in contrast, “is directly associated with muscle mass, activity, and metabolic rate,” they added, but “establishing the scientific validity of [blood creatinine levels] … remains challenging due to the progressive nature of SMA.”
The researchers conducted an observational study in 28 SMA patients, mainly males (60.7%) ages 16 to 51 (mean age, 27.8), treated for up to two years with Spinraza (nusinersen), SMA’s first approved disease-modifying therapy, by Biogen. As a control group, they included 28 sex- and age-matched healthy individuals.
Among the patients, 15 could walk independently (ambulant), while 13 could not; eight of them were unable to sit alone, and five were unable to sit independently. Most patients (17 people) had SMA type 3, eight had SMA type 2, and three had SMA type 4.
Compared with controls, SMA patients had significantly lower blood creatinine levels (67.4 vs. 23.7 micromol/L).
Creatinine levels higher in ambulant patients, those with more SMN2 copies
Over up to two years of follow-up, ambulant SMA patients had more than double the creatinine levels of those who could not walk (32 vs. 12.9 micromol/L). People with four or more copies of the SMN2 gene showed near twice the levels of creatinine than patients with fewer than four gene copies (34.1 vs. 17.2 micromol/L). A higher number of copies of SMN2, a backup gene of SMN1, is generally associated with milder disease forms, as this gene produces a partly functional SMN protein.
After adjusting for age, sex, and body mass index (a measure of body fat), patients’ motor function and motor strength significantly correlated with creatinine levels. Motor function was assessed using the Hammersmith Functional Motor Scale-Expanded (HFMSE), and motor strength on the Medical Research Council (MRC) scale.
“This suggests that as [creatinine] levels increase, there is an improvement in motor function scores and muscle strength among patients,” the researchers wrote.
Likewise, higher creatinine levels associated with an increase in ulnar muscle (upper limb) response to nerve stimulation, a measure called compound muscle action potential, or CMAP. And these levels linked with better lung function, according to measures of forced vital capacity (FVC), the maximum amount of air one can forcibly exhale after a deep breath.
Creatinine levels rose with use of Spinraza, a disease-modifying therapy
Researchers also evaluated Spinraza’s impact on blood levels of creatinine and motor function. After six months of treatment, half of 22 evaluable patients had stable or higher creatinine levels, as did 11 of 16 patients (68.8%) after 14 months of treatment, and five of six patients (83.3%) after 22 months or almost two years. Likewise, HFMSE scores remained stable or improved in 93.3% (14 of 15) of patients with six months of Spinraza’s use, and in 85.7% (six of seven patients) at almost two years.
“These results suggest that [Spinraza] can preserve or enhance motor function in adolescent and adult patients with SMA [and] reinforce the notion that [blood creatinine levels] can serve as a reliable biomarker for disease severity in SMA patients,” the researchers wrote.
Creatinine levels also were able to predict up to 83.5% of the variation in motor function measured by HFMSE, MRC, and the six-minute walking distance, a test of exercise endurance. This was significantly higher than that of other biomarkers, including SMN2 gene copy number, nerve conductance, and FVC.
“This study represents an initial endeavor in utilizing [creatinine], SMN2 copy number, FVC, CMAP, and [body mass index] to construct a predictive model for motor function in SMA patients,” the researchers wrote. “However, further investigations with larger sample sizes are imperative to validate and confirm the accuracy and reliability of our model.”
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