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Creatine is a Conditionally Essential Nutrient in Chronic Kidney Disease: A Hypothesis and Narrative Literature Review.
Post, A, Tsikas, D, Bakker, SJL
Nutrients. 2019;(5)
Abstract
To accommodate the loss of the plethora of functions of the kidneys, patients with chronic kidney disease require many dietary adjustments, including restrictions on the intake of protein, phosphorus, sodium and potassium. Plant-based foods are increasingly recommended as these foods contain smaller amounts of saturated fatty acids, protein and absorbable phosphorus than meat, generate less acid and are rich in fibers, polyunsaturated fatty acids, magnesium and potassium. Unfortunately, these dietary recommendations cannot prevent the occurrence of many symptoms, which typically include fatigue, impaired cognition, myalgia, muscle weakness, and muscle wasting. One threat coming with the recommendation of low-protein diets in patients with non-dialysis-dependent chronic kidney disease (CKD) and with high-protein diets in patients with dialysis-dependent CKD, particularly with current recommendations towards proteins coming from plant-based sources, is that of creatine deficiency. Creatine is an essential contributor in cellular energy homeostasis, yet on a daily basis 1.6-1.7% of the total creatine pool is degraded. As the average omnivorous diet cannot fully compensate for these losses, the endogenous synthesis of creatine is required for continuous replenishment. Endogenous creatine synthesis involves two enzymatic steps, of which the first step is a metabolic function of the kidney facilitated by the enzyme arginine:glycine amidinotransferase (AGAT). Recent findings strongly suggest that the capacity of renal AGAT, and thus endogenous creatine production, progressively decreases with the increasing degree of CKD, to become absent or virtually absent in dialysis patients. We hypothesize that with increasing degree of CKD, creatine coming from meat and dairy in food increasingly becomes an essential nutrient. This phenomenon will likely be present in patients with CKD stages 3, 4 and 5, but will likely be most pronouncedly present in patients with dialysis-dependent CKD, because of the combination of lowest endogenous production of creatine and unopposed losses of creatine into the dialysate. It is likely that these increased demands for dietary creatine are not sufficiently met. The result of which, may be a creatine deficiency with important contributions to the sarcopenia, fatigue, impaired quality of life, impaired cognition, and premature mortality seen in CKD.
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Creatine supplementation improves performance above critical power but does not influence the magnitude of neuromuscular fatigue at task failure.
Schäfer, LU, Hayes, M, Dekerle, J
Experimental physiology. 2019;(12):1881-1891
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Abstract
NEW FINDINGS What is the central question of this study? Does the magnitude of neuromuscular fatigue depend on the amount of work done (W') at task failure when cycling above critical power (CP)? What is the main finding and its importance? Creatine supplementation increases W' and enhances supra-CP performance, but induces similar magnitudes of neuromuscular fatigue at task failure compared to placebo. Increased W' does not lead to higher levels of neuromuscular fatigue. This supports the notion of a critical level of neuromuscular fatigue at task failure and challenges a direct causative link between W' depletion and neuromuscular fatigue. ABSTRACT The present study examined the effect of creatine supplementation on neuromuscular fatigue and exercise tolerance when cycling above critical power (CP). Eleven males performed an incremental cycling test with four to five constant-load trials to task failure (TTF) to obtain asymptote (CP) and curvature constant (W') of the power-duration relationship, followed by three constant-load supra-CP trials: (1) one TTF following placebo supplementation (PLA); (2) one TTF following creatine supplementation (CRE); and (3) one trial of equal duration to PLA following creatine supplementation (ISO). Neuromuscular assessment of the right knee extensors was performed pre- and post-exercise to measure maximal voluntary contraction (MVC), twitch forces evoked by single (Qpot ) and paired high- (PS100) and low- (PS10) frequency stimulations and voluntary activation. Creatine supplementation increased TTF in CRE vs. PLA by ∼11% (P = 0.017) and work done above CP by ∼10% (P = 0.015), with no difference (P > 0.05) in reductions in MVC (-24 ± 8% vs. -20 ± 9%), Qpot (-39 ± 13% vs. -32 ± 14%), PS10 (-42 ± 14% vs. -36 ± 13%), PS100 (-25 ± 10% vs. -18 ± 12%) and voluntary activation (-7 ± 8% vs. -5 ± 7%). No significant difference was found between ISO and either PLA or CRE (P > 0.05). These findings suggest similar levels of neuromuscular fatigue can be found following supra-CP cycling despite increases in performance time and amount of work done above CP, supporting the notion of a critical level of neuromuscular fatigue and challenging a direct causative link between W' depletion and neuromuscular fatigue.
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Creatine monohydrate supplementation during eight weeks of progressive resistance training increases strength in as little as two weeks without reducing markers of muscle damage.
Kaviani, M, Abassi, A, Chilibeck, PD
The Journal of sports medicine and physical fitness. 2019;(4):608-612
Abstract
BACKGROUND Creatine supplementation (Cr) increases strength during resistance training, but the time course of this strength increase is unclear. The aim was to determine the precise time course by which Cr could increase strength and whether Cr prevents muscle damage during eight weeks of resistance training. METHODS Young males were randomized (double blind) to Cr (N.=9, 0.07g/kg/d) and placebo (N.=9) during 8-weeks of resistance training (3 d/week). Strength was assessed across six exercises every two weeks. Venous blood samples obtained at baseline, and 24 and 48 hours after the final resistance training session were assessed for creatine kinase [CK] and lactate dehydrogenase [LDH] as measures of muscle damage. RESULTS Strength was significantly higher in the Cr versus placebo group (P<0.05) after two weeks of training for three of the six exercises (bench press, leg press, shoulder press). By the end of the eight weeks of training, strength was significantly higher in the Cr versus placebo group (P<0.05) for four of the six exercises (bench press, leg press, shoulder press, and triceps extension, but not biceps curl or lat-pulldown). Creatine supplementation did not prevent muscle damage. Indeed, muscle damage markers increased in the Cr compared to placebo group (P<0.05). CONCLUSIONS Cr increased muscular strength in as little as two weeks during a resistance training program; however, this was not accompanied by decreased muscle damage. Greater muscle damage with Cr may be due to a greater training intensity enabled by Cr supplementation. This might lead to greater protein turnover and enhanced muscle adaptation.
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Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.
Bozack, AK, Hall, MN, Liu, X, Ilievski, V, Lomax-Luu, AM, Parvez, F, Siddique, AB, Shahriar, H, Uddin, MN, Islam, T, et al
The American journal of clinical nutrition. 2019;(2):380-391
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Abstract
BACKGROUND Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. OBJECTIVE This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. DESIGN In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. RESULTS Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. CONCLUSIONS The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.
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Benefits and drawbacks of guanidinoacetic acid as a possible treatment to replenish cerebral creatine in AGAT deficiency.
Ostojic, SM
Nutritional neuroscience. 2019;(5):302-305
Abstract
Arginine-glycine amidinotransferase (AGAT) deficiency is a rare inherited metabolic disorder that severely affects brain bioenergetics. Characterized by mental retardation, language impairment, and behavioral disorders, AGAT deficiency is a treatable condition, where long-term creatine supplementation usually restores brain creatine levels and improves its clinical features. In some cases of AGAT deficiency, creatine treatment might be somewhat limited due to possible shortcomings in performance and transport of creatine to the brain. Guanidinoacetic acid (GAA), a direct metabolic precursor of creatine, has recently been suggested as a possible alternative to creatine to tackle brain creatine levels in experimental medicine. AGAT patients might benefit from oral GAA due to upgraded bioavailability and convenient utilization of the compound, while possible drawbacks (e.g. brain methylation issues, neurotoxicity, and hyperhomocysteinemia) should be accounted as well.
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Effects of high-velocity resistance training and creatine supplementation in untrained healthy aging males.
Bernat, P, Candow, DG, Gryzb, K, Butchart, S, Schoenfeld, BJ, Bruno, P
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2019;(11):1246-1253
Abstract
The purpose was to investigate the effects of high-velocity resistance training (HVRT) and creatine supplementation in untrained healthy aging males. Participants were randomized to supplement with creatine (0.1 g·kg-1·day-1 of creatine + 0.1 g·kg-1·day-1 of maltodextrin) or placebo (0.2 g·kg-1·day-1 of maltodextrin) during 8 weeks of HVRT. Prior to and following HVRT and supplementation, assessments were made for muscle strength, muscle thickness, peak torque, and physical performance. There was a significant increase over time for all measures of muscle strength (p < 0.001), muscle thickness (p < 0.001), and some measures of peak torque (knee flexion; 1.05 and 3.14 rad/s; p < 0.001) and physical performance (balance board time-to-completion; p = 0.017). There was a group × time interaction for leg press strength (p = 0.044) and total lower-body strength (leg press, knee flexion, knee extension combined; p = 0.039). The creatine group experienced greater gains in leg press and total lower-body strength compared with the placebo group, with no other differences. HVRT increases muscle strength, muscle thickness, and some measures of peak torque and physical performance in untrained healthy aging males. The addition of creatine supplementation to HVRT further augments the gains in leg press and total lower-body strength. Novelty High-velocity resistance training increases muscle mass and performance. Creatine supplementation increases lower-body muscle strength. High-velocity resistance training and creatine supplementation are safe interventions for aging adults.
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Prognostic value of serum creatine level in patients with vulvar cancer.
Schwameis, R, Postl, M, Bekos, C, Hefler, L, Reinthaller, A, Seebacher, V, Grimm, C, Polterauer, S, Helmy-Bader, S
Scientific reports. 2019;(1):11129
Abstract
Vulvar cancer is a rare malignancy with poor prognosis that generally occurs in elderly patients. The individual prognosis is difficult to assess. Serum creatinine levels are frequently elevated in elderly patients. Recent evidence have shown shown that - besides indicating kidney impairment - serum creatinine levels may be used to predict the survival in cancer patients. Several studies observed an association between elevated serum creatinine levels and poor prognosis in patients with solid tumors. In this retrospective cohort study, serum creatinine levels were evaluated in 170 patients with invasive vulvar cancer. Serum creatinine levels were correlated to established clinicopathologic factors. Univariate and multivariate survival analysis were performed. Elevated serum creatinine levels (>1.2 mg/dl) were significantly associated with both poor disease specific and overall survival. Three year overall survival rates were 74.8% and 32.5% for patients with serum creatinine levels of ≤ and >1.2 mg/dl, respectively. In a multivariate survival model, serum creatinine levels were significantly associated with overall survival independent of tumor stage and patients' age. In conclusion, pretherapeutic serum creatinine levels may be useful as an independent prognostic parameter in patients with vulvar cancer.
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Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis.
de Souza E Silva, A, Pertille, A, Reis Barbosa, CG, Aparecida de Oliveira Silva, J, de Jesus, DV, Ribeiro, AGSV, Baganha, RJ, de Oliveira, JJ
Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2019;(6):480-489
Abstract
Creatine supplements are intended to improve performance, but there are indications that it can overwhelm liver and kidney functions, reduce the quality of life, and increase mortality. Therefore, this is the first systematic review and meta-analysis study that aimed to investigate creatine supplements and their possible renal function side effects. After evaluating 290 non-duplicated studies, 15 were included in the qualitative analysis and 6 in the quantitative analysis. The results of the meta-analysis suggest that creatine supplementation did not significantly alter serum creatinine levels (standardized mean difference = 0.48, 95% confidence interval 0.24-0.73, P = .001, I2 = 22%), and did not alter plasma urea values (standardized mean difference = 1.10, 95% confidence interval 0.34-1.85, P = .004, I2 = 28%). The findings indicate that creatine supplementation does not induce renal damage in the studied amounts and durations.
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A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effectiveness of a Food Supplement Containing Creatine and D-Ribose Combined with a Physical Exercise Program in Increasing Stress Tolerance in Patients with Ischemic Heart Disease.
Derosa, G, Pasqualotto, S, Catena, G, D'Angelo, A, Maggi, A, Maffioli, P
Nutrients. 2019;(12)
Abstract
The aim of this study is to establish whether a supplement of creatine and ribose combined with a physical exercise program can improve the total work capacity during exercise in a population of patients with known ischemic heart disease. A double-blind, six-month study was designed in which 53 patients were enrolled and randomized to take either a nutraceutical composition containing creatine, D-ribose, vitamin B1, and vitamin B6 (active treatment) or the placebo. Both the nutraceutical supplement and the placebo were supplied by Giellepi S.p.A. Health Science in Lissone, Italy. After six months of study, the cardiac double product at the peak of the load, the delta double product, and the chronotropic index were higher in the active treatment group than in the placebo group. We can conclude that a supplementation with creatine, D-ribose, vitamin B1, and vitamin B6, in addition to standard therapy and a physical exercise program, seems to be helpful in improving exercise tolerance compared to the placebo in a population with cardiovascular disease. However, this needs to be further studied, given that there is no clear evidence that the double product can be used as a surrogate measure of exercise tolerance.
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D3 -Creatine dilution and the importance of accuracy in the assessment of skeletal muscle mass.
Evans, WJ, Hellerstein, M, Orwoll, E, Cummings, S, Cawthon, PM
Journal of cachexia, sarcopenia and muscle. 2019;(1):14-21
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Abstract
Sarcopenia has been described as the age-associated decrease in skeletal muscle mass. However, virtually every study of sarcopenia has measured lean body mass (LBM) or fat free mass (FFM) rather than muscle mass, specifically. In a number of published sarcopenia studies, LBM or FFM is referred to as muscle mass, leading to an incorrect assumption that measuring LBM or FFM is an accurate measure of muscle mass. As a result, the data on the effects of changes in LBM or FFM in older populations on outcomes such as functional capacity, disability, and risk of injurious falls have been inconsistent resulting in the conclusion that muscle mass is only weakly related to these outcomes. We review and describe the assumptions for the most commonly used measurements of body composition. Dual-energy X-ray absorptiometry (DXA) has become an increasingly common tool for the assessment of LBM or FFM and appendicular lean mass as a surrogate, but inaccurate, measurement of muscle mass. Other previously used methods (total body water, bioelectric impedance, and imaging) also have significant limitations. D3 -Creatine (D3 -Cr) dilution provides a direct and accurate measurement of creatine pool size and skeletal muscle mass. In a recent study in older men (MrOS cohort), D3 -Cr muscle mass was associated with functional capacity and risk of injurious falls and disability, while assessments of LBM or appendicular lean mass by DXA were only weakly or not associated with these outcomes. Inaccurate measurements of muscle mass by DXA and other methods have led to inconsistent results and potentially erroneous conclusions about the importance of skeletal muscle mass in health and disease. The assessment of skeletal muscle mass using the D3 -Cr dilution method in prospective cohort studies may reveal sarcopenia as a powerful risk factor for late life disability and chronic disease.