Creatine is a naturally occurring nitrogen compound synthesized from three amino acids and mainly located in skeletal muscle. Its phosphorylated form plays a pivotal role in energy metabolism by supplying phosphate group to ADP to regenerate ATP. Since 1992, a series of studies has suggested that creatine supplementation may be an effective ergogenic substance (6). Feeding 20-30 g creatine per day for several days is a common procedure that can indeed induce an increase in human skeletal muscle total creatine and phosphorylcreatine. Nowadays, creatine supplements are now used worldwide by healthy individuals and athletes to increase their maximal performance and to gain better adaptations during intense training sessions (see reviews 1, 11).
Recently, it has been claimed by Pritchard and Kalra (15) that oral creatine supplements may lead to renal dysfunction. Moreover, press releases have attributed deaths of American wrestlers to creatine supplementation. Both assertions appeared to be overreacting positions. Indeed, we demonstrated that short-term (12) and medium term (13) creatine supplementation in men does not appear to have any detrimental effect on the renal responses of healthy adults. Nevertheless, it has been suggested that a long-term, nitrogen-rich diet might itself induce renal hyperfiltration and thereby contribute to the functional and structural deterioration of the kidney (2). Theoretically, the high nitrogen content (32%) of creatine could add some strain on the kidney if taken in large excess for a long period of time.
To shed light on this specific aspect, we investigated the effect of long-term oral creatine ingestion by highly trained athletes on the estimated glomerular function, urea clearance, and protein excretion rate.
Subjects. Eight young men and one women (24 ± 3 yr old), in healthy condition, participated in the present investigation. Being athletes in track and field and volleyball on the national and international levels, they regularly participated in strenuous exercise training (12-18 h·wk−1) for the last few years (5-10 yr). Theses subjects have been chosen as voluntary and spontaneous regular consumers of creatine monohydrate (Table 1). Eighty-five male students in physical education and physical therapy, who did not consume any ergogenic supplements, served as a control group. The experimental protocol was approved by the Ethics Committee of the Faculties of Medicine of the Université Libre de Bruxelles and of the Université Catholique de Louvain, and all subjects gave informed written consent before participating in the study.
Creatine supplementation. Our highly trained athletes consumed regularly creatine monohydrate of different origins (organic synthesis). The powder was diluted in hot water, and for some individuals an additional load of glucose or maltodextrine was added to the Cr. Individual doses from 1 to 20 g creatine were taken up to 1 to 4 doses per day. Altogether, daily doses from 1 to 80 g·d−1 were ingested every single day of the week for a period from 10 months to 5 yr. Side effects were almost absent but muscle cramps (one subject) and headache (one subject) were occasionally reported. However, we do not have evidence that these slight side effects were really related to creatine supplementation.
Blood and urine samples. All subjects reported to the laboratory around 0800 h with a 24-h urine collection. They did not consume creatine during the 16 h before the blood sampling. Sodium merthiolate was added to each urine sample to prevent bacteria growth. Blood samples were drawn from the antecubital vein into EDTA K3 Vacutainer tubes (Becton-Dickinson, Le Pont de Claix, France), the subjects being in a seated position. Plasma was separated by centrifugation at 2200 × g during 10 min. All samples were assayed the day of collection.
Biochemical analyses. Creatine and creatinine were determined in plasma and urine using an enzymatic colorimetric test PAP (Boehringer Mannheim, Mannheim, Germany). Creatine was assayed by omission of creatininase in the test tube. Urea was analyzed in both biological fluids by an enzymatic technique (Sigma Diagnostic-Urea Nitrogen No. 640, St. Louis, MO). Albumin in urine was assayed by an immunological method (9) (Turbiquant Albumin urine, Behring). Plasma albumin was determined by a colorimetric assay (5). The urine excretion rates, expressed in units·min−1, were calculated using the 24-h urine output whereas the clearance values for creatine, urea, and albumin were calculated as the ratio of urine excretion rate to plasma concentration.
Statistical analyses. Mann-Whitney's two-sample rank sum test was used to compare any difference between the creatine group and the control group (P < 0.05). The results are given as mean ± SEM. All calculations were made using StatView statistical package.
Table 2 reports values obtained in the control and the creatine supplementation groups. There were no statistical differences between the two groups for plasma contents of creatine, creatinine, urea, and albumin. The creatine group had a urine creatine excretion rate and a creatine (μmol)) to creatinine (mmol) ratio far away from the values recorded in the control group. This clearly showed that the first group was a heavy consumer of exogenous creatine supplements. Urine excretion rates for creatinine, urea, and albumin were within the normal range of a healthy young population in both groups. Creatine clearance in the creatine consumer group was similar to the glomerular filtration rate estimated from the creatinine clearance. The other clearance measurements (creatinine, urea, and albumin) did not differ when comparing control and creatine supplement groups. Thus, the glomerular filtration rate (creatinine clearance), tubular reabsorption (urea clearance), and glomerular membrane permeability (albumin clearance) were normal in both groups rejecting any detrimental effect of creatine supplementation on these renal parameters.
It has been reported that excess dietary protein (17) and amino acid loading (3,10) are associated with renal hyperfiltration, vasodilation, and inhibition of tubular protein reabsorption. These effects can induce proteinuria and progressive kidney impairments. Very recently, Pritchard and Kalra (15) have proposed that oral creatine supplementation will lead to renal dysfunction. Indeed, these authors reported that their one subject, who had glomerulosclerosis for 8 yr, being treated with the nephrotoxic cyclosporin drug for the past 5 yr, had substantial renal dysfunction after consuming creatine for 7 wk. This report and the widespread use of this ergogenic product among athletes meant that the safety of creatine use could be questioned.
Previously we investigated the potential kidney dysfunction induced by oral creatine looking at short-term (5 d) (12) and medium-term (63 d) (13) supplementation. We demonstrated that, under these circumstances, oral creatine supplements did not affect kidney function in healthy individuals. The present report extends these observations by investigating the long-term effects (10 months to 5 yr) of regular oral creatine supplementation. An increase in the urinary creatinine output has been reported during 5 d (7), 36 d (16), and 90 d (4) of creatine supplementation. However, two other reports did not observe any modification of creatinine excretion after 5 d (8) and 10 wk (18) of creatine supplements. Our present study on 10 months to 5 yr creatine supplements confirms these latter observations. The lack of increase in creatinine output under creatine supplementation may be due to the large excess of urine excretion of this dietary supplement. Moreover, Vandenberghe et al. (18) mentioned similar urinary urea output values between creatine and placebo groups as we did. It is also interesting to note that the renal creatine clearance of the supplementation group is similar to their glomerular filtration rate. This observation points out the efficient plasma clearance of excess creatine consumption that is not taken up by the intracellular compartment. The estimated glomerular filtration rate (creatinine) and the urine excretion of plasma albumin remained within the normal range of a healthy young population (14). No sign of hyperfiltration was observed under these conditions.
Thus, the present report confirms our previous investigations that did not postulate any detrimental effect of creatine supplementation by healthy individuals, up to 5 yr. Nevertheless, a more extended survey should be addressed in the near future and it would be worth to stress that those who have suspected renal dysfunction should avoid any creatine supplementation.
We thank the Direction Générale des Sports (Communauté Française de Belgique) for their support as well as Mrs F. Louppe-Reding for her efficient technical help.
1. Balsom, P. D., K. Söaderlund, and B. Ekblom. Creatine in humans with special reference to creatine supplementation. Sports Med.
2. Brenner, M. B., T. W. Meyer, and T. H. Hostetter. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation and intrinsic renal disease. N. Engl. J. Med.
3. Coppo, R., M. G. Porcellini, B. Gianoglio, et al. Glomerular preselectivity to macromolecules in reflux nephropathy: microalbuminuria during acute hyperfiltration due to amino acid infusion. Clin. Nephrol.
4. Crim, M. C., D. H. Calloway, and S. Margen. Creatine metabolism in men: urinary creatine and creatinine excretions with creatine feeding. J. Nutr.
5. Doumas, B. T., W. A. Watson, and H. G. Briggs. Albumin standards and the measurement of serum albumin with bromcresol green. Clin. Chim. Acta
6. Harris, R. C., K. Soderlund, and E. Hultman. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin. Sci.
7. Hultman, E., K. Soderlund, J. A. Timmons, G. Cederblad, and P. L. Greenhaff. Muscle creatine loading in men. J. Appl. Physiol.
8. Maganaris, C. N., and R. J. Maughan. Creatine supplementation enhances maximum voluntary isometric and endurance capacity in resistance trained men. Acta Physiol. Scand.
9. Metzmann, E. Protein quantitation of both branches of the Heidelberger curve by monitoring the kinetic of immunoprecipitation. Behring Inst. Mitt.
10. Mogensen, C. E., and K. Solling. Studies on renal tubular protein reabsorption:partial and near complete inhibition by certain amino acids. Scand. J. Clin. Lab. Invest.
11. Mujika, I., and S. Padilla, Creatine supplementation as an ergogenic aid for sports performance in highly trained athletes
. Int. J. Sports Med.
12. Poortmans, J. R., H. Auquier, V. Renaut, A. Durussel, M. Saugy, and G. R. Brisson. Effects of short-term creatine supplementation on renal responses in men. Eur. J. Appl. Physiol.
13. Poortmans, J. R., and M. Francaux. Renal dysfunction accompanying oral creatine supplements: reply. Lancet
14. Poortmans, J. R., and J. Vanderstraeten. Kidney function during exercise in healthy and diseased humans. Sports Med.
15. Pritchard, N. R., and P. A. Kalra. Renal dysfunction accompanying oral creatine supplements. Lancet
16. Rossiter, H. B., E. R. Cannell, and P. M. Jakemen. The effect of oral creatine supplementation
on the 1000-m performance of competitive rowers. J. Sports Sci.
17. Tolins, J. P., P. J. Shultz, G. Westberg, and L. Raij. Renal hemodynamic effects of dietary protein in the rat: role of nitric acid. J. Lab. Clin. Med.
18. Vandenberghe, K., M. Goris, P. Van Hecke, M. Van Leemputte, L. Vangerven, and P. Hespel. Long-term creatine intake is beneficial to muscle performance during resistance training. J. Appl. Physiol.