Longitudinal Assessment of Creatine Kinase, Creatine/Creatinine ratio , and Myostatin as Monitoring Biomarkers in Becker Muscular Dystrophy
Nienke M. van de VeldeZaïda KoeksMirko SignorelliNisha VerweyMaurice OverzierJaap BakkerGautam SajeevJames SignorovitchValeria RicottiJan J.G.M. VerschuurenKristy J. BrownPietro SpitaliE. Niks
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Abstract:
Background and Objectives:
The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in three muscle-enriched biomarkers in serum of BMD patients over 4 years-time and studied associations with disease severity, disease progression and dystrophin levels in BMD.Methods:
We quantitatively measured creatine kinase (CK) using the IFCC reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography – tandem mass spectrometry (LC-MS/MS) and myostatin with ELISA in serum, and assessed functional performance using North Star Ambulatory Assessment (NSAA), ten-meter run velocity (TMRv), six-minute walking test (6MWT), and Forced Vital Capacity (FVC) in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance were analyzed using linear mixed models.Results:
Thirty-four patients with 106 visits were included. Eight patients were non-ambulant at baseline. Cr/Crn and myostatin were highly patient-specific (intraclass correlation coefficient for both=0.960). Cr/Crn was strongly negatively correlated, while myostatin was strongly positively correlated with NSAA, TMRv and 6MWT (Cr/Crn rho=-0.869 to -0.801 and myostatin rho=0.792 to 0.842, all p<0.001). CK showed a negative association with age (p=0.0002) but was not associated with patients' performance. Cr/Crn and myostatin correlated moderately with average annual change of 6MWT (rho=-0.532 and 0.555, p=0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv and 6MWT.Discussion:
Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers.Keywords:
Creatine kinase
Creatine
Myostatin
AbstractKuhlbäck, B., Pasternack, A., Launiala, K. & Stenberg, M. Serum Creatine and Creatinine in Children and Adolescents. Scand. J. clin. Lab. Invest. 22, 37-40, 1968. The creatine and creatinine concentration in the serum was studied in 229 children and adolescents aged 0-19 years. Almost normal adult values were recorded immediately after birth. At the age of half a year to 15 years the serum creatine level was high and the serum creatinine level was low. A steady decrease in serum creatine and increase in creatinine was observed. The ratio creatine/creatinine did not drop to under 1 until the age of 14-15 years. Completely normal adult values were only noted in those aged 16-20 years. The possible causes of these changes are discussed. The low serum creatinine concentration in children should be borne in mind on evaluating renal function and its possible changes in childhood.Key Words: Adolescentschildhoodcreatinecreatininerenal function
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Typical HPLC chromatograms of creatine and creatinine for (a) standards, (b) urine sample, and (c) urine sample spiked with both creatine and creatinine standards: 1, creatine; 2, creatinine; IS, hypoxanthine.
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A survey of the creatine and creatinine excretion of large numbers of mentally defective patients in circumstances which precluded both keeping them on creatine-free diet and the obtaining of 24-hour specimens, led Penrose and Pugh (1939) to the use of the creatine creatinine ratio in early morning specimens of urine as an index of the metabolism of these substances in each patient, as compared with controls. The use of the ratio was found to yield results of qualitative significance. Patients suffering from conditions known to affect creatine-creatinine metabolism, such as muscular dystrophies, diplegias, and hyperthyroidism, were readily picked out, and the creatinuria of children was marked; conclusions could be drawn as to the creatine-creatinine metabolism in certain other conditions. In the above survey the numbers allowed of statistical treatment to a considerable extent, and this confirmed the validity of the conclusions drawn from the ratio.
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OBJECTIVE: To examine the effect of creatine supplementation on renal function and estimates of creatinine clearance. DATA SOURCES: A MEDLINE search was conducted (1966—September 2004) using the key terms creatine, creatinine, kidney function tests, drug toxicity, and exercise. Relevant articles were cross-referenced to screen for additional information. DATA SYNTHESIS: Supplementation with creatine, an unregulated dietary substance, is increasingly common in young athletes. To date, few studies have evaluated the impact of creatine on renal function and estimates of creatinine clearance. Because creatine is converted to creatinine in the body, supplementation with large doses of creatine may falsely elevate creatinine concentrations. Five studies have reported measures of renal function after acute creatine ingestion and 4 after chronic ingestion. All of these studies were completed in young healthy populations. Following acute ingestion (4–5 days) of large amounts of creatine, creatinine concentrations increased slightly, but not to a clinically significant concentration. Creatinine is also only minimally affected by longer creatine supplementation (up to 5.6 y). CONCLUSIONS: Creatine supplementation minimally impacts creatinine concentrations and renal function in young healthy adults. Although creatinine concentrations may increase after long periods of creatine supplementation, the increase is extremely limited and unlikely to affect estimates of creatinine clearance and subsequent dosage adjustments. Further studies are required in the elderly and patients with renal insufficiency.
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Abstract. Serum and urinary creatine and creatinine have been studied in eight patients with paralytic poliomyelitis. The serum and urinary creatine concentrations were strikingly high, while the corresponding creatinine concentrations were extremely low. The creatine/creatinine ratio showed an obvious change in both the serum and urine as compared to normal control values. The cause of the changes observed and their clinical implications are discussed.
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When muscle tissue is allowed to autolyze, creatine is transformed to creatinine at a constant rate. The velocity of this reaction increases with a rise in temperature, although practically negligible at 0° C. The rate of formation at body temperature is nearly sufficient to account for the daily elimination of creatinine. The velocity of the reaction is increased by acids but not reduced by Henderson's neutral phosphate mixture. Added creatine experiences the same fate as the creatine originally present, while added creatinine inhibits the reaction, or if added in sufficient quantity causes it to proceed in the opposite direction. Pure solutions of creatine and creatinine experience the same transformations, although much more slowly. On the long standing of pure solutions there seems to be a slight loss in total creatinine (from both creatine and creatinine). This appears to be due in part to a transformation to urea. Whether or not these phenomena are vital factors in the formation of creatinine in the body, we are unprepared to say. To obtain further light on this point, experiments have been conducted on nephrectomized animals. The creatine and creatinine content of the various body tissues have been determined several days after a double nephrectomy. In certain of these experiments creatine and creatinine have been injected. Some what similar deductions may be drawn from our experiments in vivo to those in vitro; although there are certain differences between the two types of experiments, the significances of which are not as yet entirely clear to us.
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