Creatine monohydrate treatment alleviates muscle cramps associated with haemodialysis

Chiz-Tzung Chang, Chin-Herng Wu, Chih-Wei Yang, Jeng-Yi Huang and Mai-Szu Wu

Department of Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Muscle cramp is a common complication of haemodialysis. The exact mechanism of this complication is still unknown. Many approaches have been used to relieve the muscle cramping but have had variable effects. One of the possible mechanisms of haemodialysis-associated muscle cramps (HAMC) is the disturbance of muscle energy metabolism. Creatine monohydrate can enhance muscle metabolism. We evaluated the clinical effect of creatine monohydrate on HAMC.

Methods. Ten patients with frequent muscle cramps during haemodialysis were randomly selected into two groups, control and placebo. In a double-blind manner, 12 mg of creatine monohydrate or placebo was given to each patient before each dialysis session for 4 weeks. The incidence of muscle cramp during haemodialysis was compared between the two groups. Dialysis adequacy, haemodynamic status, and side-effects were also evaluated. We continued to observe and compare the patients during a 4-week washout period to verify the effect of creatine monohydrate.

Results. The frequency of symptomatic muscle cramps decreased by 60% in the creatine monohydrate treatment group (6.2±0.8 vs 2.6±1.8 times/4 weeks, P<0.05) during the treatment period. This decreasing incidence of muscle cramps disappeared in the washout period in the creatine group (6.6±1.1 times/4 weeks). There was no difference in the incidence of muscle cramps in the placebo group. The haematocrit, Kt/V, serum albumin, and haemodynamics remained unchanged in both groups during the treatment and washout periods. Serum creatinine increased slightly after creatine monohydrate treatment (10.7±3.2 vs 12.4±3.2 mg/dl, P<0.05). No adverse effect was found in either group during the treatment and washout periods.

Conclusion. These data suggest that creatine monohydrate can reduce the incidence of HAMC and that it may be a safe agent.

Keywords: creatine monohydrate; haemodialysis; muscle cramps; muscle metabolism; placebo control; single-unit study



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Painful muscle cramps often complicate haemodialysis. They may occur in 35–86% of haemodialysis patients [1] and can be severe enough to compromise haemodialysis treatment [2]. The exact mechanism of intradialysis muscle cramping is still unknown, and a number of palliative measures have been employed without consistent effects [3]. Subnormal muscle metabolism is thought to be one of the major mechanisms underlying these muscle cramps [4]. Excessive dialysis ultrafiltration, intradialytic hypotension, or tissue hypoxia may lead to an abnormal utilization of energy by muscles and thus result in muscle cramps [5]. Creatine monohydrate has been used to increase muscle strength and work performance in elite athletes [6]. It may cause better muscle metabolism by increasing muscle creatine phosphate stores. Creatine phosphate can release a phosphate group to ADP and turn it into ATP [7], which is the major source of muscle energy. With those facts in mind, one might ask if administration of creatine monohydrate could alleviate the haemodialysis-associated muscle cramps (HAMC). To answer that question, we conducted a prospective randomized study to examine the effect of oral creatine monohydrate on HAMC.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our cohort comprised 10 patients who were on maintenance haemodialysis in a single dialysis unit in University Hospital (Chang Gung Memorial Hospital, Taipei, Taiwan), and who had experienced frequent intradialytic muscle cramps. After being enrolled in the study and with their informed consent, the patients were randomly assigned to the creatine and placebo groups, each of five patients. Each group comprised three females and two males, the creatine group with an average age of 57.4±18.3 years, and the placebo group with an average age of 56.0±7.9 years. No patient was a smoker or alcohol user. The cause of end-stage renal disease in all 10 subjects was chronic glomerulonephritis, and none of them was on anti-hypertensive medications during the study.

Hollow-fibre dialysers were used with a bicarbonate-based dialysate, in which sodium concentration was 140 mmol/l and calcium 1.75 mmol/l. A muscle cramp was defined as a painful involuntary muscle contraction that lasted more than 1 min during the dialysis [8]. An intradialytic hypotensive episode was a decrease of more than 15 mmHg in either systolic or diastolic blood pressure. Following a double-blind protocol, either creatine monohydrate powder (Oakdale NY) powder or placebo—12 g dissolved in 100 ml water—was given to the patients 5 min before starting haemodialysis. The doses were administered by attending nurses in order to ensure compliance. The occurrence of painful muscle cramps was recorded. Blood pressure was measured every 30 min. Plasma creatinine, albumin, haematocrit, and Kt/V were checked after 4 weeks of treatment. Kt/V was calculated as described by Jackson [9].

To further confirm that any observed change was related to the administration of creatine monohydrate, the same clinical and laboratory parameters were followed for an additional 4 weeks, considered as a washout period.

Results are expressed as means±SD. Notable differences between the two groups were analysed by Student's t-test and one-way ANOVA. We used the SPSSTM program for statistical analysis. A P value <0.05 was considered significant.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The baseline haemodynamic and biochemical parameters before creatine monohydrate or placebo treatment were similar in both groups (Table 1Go). No increase in dry weight was found in the creatine group after creatine monohydrate treatment (before vs after: 63.9±18.3 vs 63.9±18.3 kg, P>0.05). There was no significant change in the pre-dialysis blood pressures and ultrafiltration rates. The occurrence of a hypotensive episode was slightly decreased in the creatine group, but without statistical significance (control vs creatine: 7.2±1.8 vs 5.8±2.6 times/4 weeks, P>0.05). These results indicate that short-term oral creatine monohydrate intake did not induce significant haemodynamic changes during haemodialysis. The Kt/V, serum albumin, and haematocrit did not change in the groups either before or during the treatment (Table 1Go). The data suggested that creatine monohydrate did not influence the prescribed dialysis dosage, nutritional status, and erythropoiesis in our patients. The episodes of muscle cramps were decreased by 60% during the treatment period in the creatine group (control vs creatine: 6.4±0.9 vs 2.6±1.8 times/4 weeks, P<0.05). We did not observe any decrease in cramps in the placebo group (control vs placebo: 6.6±1.1 vs 6.2±0.8 times/4 weeks, P>0.05) (Figure 1Go). Serum creatinine increased by 16% in the creatine group (control vs creatine: 10.7±3.2 vs 12.4±3.2 mg/dl, P<0.05) (Table 1Go). The increase in serum creatinine was not associated with anorexia, nausea, vomiting, or other uraemic symptoms.


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Table 1.  Haemodynamic and biochemical values before and during treatment periods in creatine and placebo groups

 


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Fig. 1.  Muscle-cramp incidence before treatment, during treatment, and in the washout period in creatine (•) and placebo ({circ}) groups.

 
To further confirm that the observed effect comes from creatine, we continued to follow the patients after treatment period for an additional 4 weeks, considered as a washout period. During that 4-week washout period, the incidence of muscle cramps in the creatine group increased to previous levels (6.2±0.8 times/4 weeks) (Figure 1Go). This incidence is almost the same as that prevalent before treatment (washout vs before: 6.2±0.8 vs 6.4±0.9 times/4 weeks). All other parameters of the washout period were equal to those before treatment (Table 1Go). Serum creatinine returned to pre-treatment baseline values after the washout period in the creatine group (washout vs before: 10.2±3.0 vs 10.7±3.2 times/4 weeks) (Figure 2Go).



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Fig. 2.  Serum creatinine values before treatment, during treatment, and in the washout period in creatine (•) and placebo ({circ}) groups.

 
There were no observed side-effects such as nausea or vomiting during the 4-week treatment period. No nausea and vomiting appeared during the 4-week treatment period in either the placebo or the creatine groups. Serum GPT levels were the same before and during creatine monohydrate treatment (15.5±3.6 vs 14.4±2.7 IU/l). Four of the five patients in the creatine group asked to continue the creatine monohydrate treatment after the end of the study.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Muscle cramp is one of the most common and uncomfortable complications experienced during haemodialysis. The exact mechanism of these muscle cramps is still unknown. It is often associated with intradialytic hypotension, excessive ultrafiltration, or elevation of serum creatine kinase [10]. The acute management of this painful complication has included hypertonic glucose, saline, or mannitol with inconsistent and variable effects [11]. Higher dialysate sodium concentrations also reduce the incidence of HAMC. Profiling of dialysate sodium and bicarbonate also reduces cramping significantly [2,5]. Long-term administration of vitamin E [11], quinine [11], and L-carnitine [12] have also been used to decrease the cramp but with equivocal results. These agents have in common the effects of increasing muscle energy usage and strength. ATP splits into ADP and phosphate and liberates the energy for muscle work. Abnormal muscle energy metabolism with subsequent lactic acid formation may be the cause of muscle weakness and painful muscle cramping [13].

Creatine monohydrate has long been used by elite athletes to increase muscle mass and improve performance [14]. It can increase muscle phosphocreatine stores and transfer its phosphate group to ADP when muscles need energy [15]; the need for anaerobic generation of ATP via the lactate pathway will be decreased [16], and the muscle membrane can be stabilized and cramps reduced as muscle energy utilization is improved [17].

In our study, creatine monohydrate significantly decreased the incidence of HAMC. There was no differences in dry weight, pre-dialysis blood pressure, ultrafiltration rate, and hypotension episodes in the creatine group before treatment or during the treatment, and washout periods. Haemodynamic factors were identical in the two groups. The results indicate that haemodynamic change did not play a role in the observed effect of creatine on muscle cramping. We believe that the reduction in muscle cramping may come from better utilization of energy in the muscle.

Paradoxically, creatine monohydrate can lead to muscle cramp when used in individuals with normal renal function. The possible mechanism of that side-effect is the change of cell volume induced by creatine. Creatine may enter muscle cells and increase intracellular osmolality. The accumulation of creatine within muscle cells leads to fluid shift from the extracellular compartment to intracellular spaces. The resulting shrinkage of extracellular fluid volume causes muscle cramping [18]. This volume-shifting mechanism might be compromised during haemodialysis by the concomitant controlled ultrafiltration, which simultaneously increases extracellular osmolality and decreases extracellular fluid.

Serum creatinine may increase in patients with renal insufficiency who take creatine monohydrate [19]. There was a small increase in serum creatinine levels in our patients. However, they developed no anorexia, nausea, vomiting, or other uraemic symptoms in 4 weeks of creatine administration. Further long-term observation may be indicated to determine the clinical significance of elevated pre-dialysis creatinine. There were no changes in liver enzymes and serum albumin during 4 weeks of treatment, which may indicate the absence of hepatic side-effects as reported in the literature [20]. Creatine monohydrate may be safe in uraemic patients, at least for short-term use.

We conclude that creatine monohydrate might be used for the treatment of HAMC and that in the short-term this agent is safe for patients on maintenance haemodialysis. However, the number of our patients was small and the follow-up period short. Further long-term, large-scale studies are mandatory to confirm the effects and safety of creatine monohydrate therapy in HAMC.



   Notes
 
Correspondence and offprint requests to: Mai-Szu Wu, Division of Nephrology, Chang Gung Memorial Hospital, 199 Tun Hwa North Road, Taipei, Taiwan. Email: maisuwu{at}ms9.hinet.net Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 9.11.01
Accepted in revised form: 12. 6.02





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