Effects of L-Carnitine Supplementation in Maintenance Hemodialysis Patients: A Systematic Review
Jean-Marc Hurot*,
Michel Cucherat,
Margaret Haugh and
Denis Fouque*
*Department of Nephrology, Hôpital Edouard Herriot, Lyon, France; and Centre Cochrane Français, Centre Léon Bérard, Lyon, France.
Correspondence to: Dr. Denis Fouque, Department of Nephrology, Hôpital E.Herriot, 69437 Lyon Cedex 03, France. Phone: +33-4-72-11-02-02; Fax: +33-4-72-11-02-03; E-mail: denis.fouque{at}chu-lyon.fr
ABSTRACT. There are many causes for carnitine depletion duringmaintenance hemodialysis. Supplementation with L-carnitine inanimals has been associated with improvement in some abnormalitiesalso present in chronic renal failure. However, it is stillcontroversial whether restoring plasma or tissue carnitine willcorrect clinical or biologic symptoms observed in maintenancehemodialysis. A systematic review is here performed to determinethe effects of L-carnitine in maintenance hemodialysis patients.Eighty-three prospective trials were identified from 1978 to1999 in which L-carnitine was randomly allocated in 21 trials.Change in serum triglycerides, cholesterol fractions, hemoglobinlevels, erythropoietin dose, and other symptoms (muscle function,exercise capacity, and quality of life) were examined. A totalof 482 patients in 18 trials were considered for analysis. Therewas no effect of L-carnitine on triglycerides, total cholesterol,or any of its fractions. Before the erythropoietin (EPO) era,L-carnitine treatment was associated with improved hemoglobin(P < 0.01) and with a decreased EPO dose (P < 0.01) andimproved resistance to EPO when patients routinely receivedEPO. Muscle function, exercise capacity, and quality of lifecould not be reliably assessed because of the noncombinablenature of end points and the limited number of trials. In conclusion,L-carnitine cannot be recommended for treating the dyslipidemiaof maintenance hemodialysis patients. By contrast, this reviewsuggests a promising effect of L-carnitine on anemia management.The route of L-carnitine administration should be evaluatedbecause there is no evidence as to the most efficient methodof administration in maintenance hemodialysis.
L-carnitine is a small compound (molecular weight, 162 D) foundmostly in milk and meat. The liver also represents one of themain sources of endogenous carnitine synthesis from lysine,methionine and ascorbate, niacin, pyridoxine, and Fe2+ (25).Carnitine is captured and stored by the muscle because thereis no carnitine synthesis in muscle. Carnitine is metabolizedfor numerous metabolic purposes, and among these, the most criticalare the regulation of ketogenesis (26), adaptation of mitochondrialenergy control, free fatty acid (FFA) transport, and clearance(27). Regulation of FFA ß-oxidation occurs throughan adaptation of the FFA mitochondrial content from an exitof acyl and acetyl moieties, thus modifying the esterified carnitine(EC)/free carnitine (FC) ratio. The carnitine shuttle allowsan adequate mitochondrial FFA content and protects against adownregulation of ß-oxidation observed in certainconditions such as metabolic acidosis, hypoxemia, or impairedglucose metabolism.
During chronic renal failure and before maintenance hemodialysis,total carnitine accumulates in response to a decreased renalclearance of EC moieties (28). Furthermore, there is an increasedneed for FC in response to hypoxemia or acidosis. By contrast,patients undergoing maintenance hemodialysis not uncommonlypresent with serum carnitine deficiency (29). Indeed, serumcarnitine rapidly decreases to 40% of baseline level duringthe dialysis session (12,30). It is more difficult to assessmuscle carnitine for technical reasons and because of a greatvariability of muscle carnitine in healthy volunteers. In addition,biopsies have been performed at nonstandardized time pointsfrom the beginning of the dialysis session, preventing any comparisonbetween studies (31,32). The role of dialysis membranes on carnitineloss into the dialysate is also uncertain. It should be emphasized,however, that carnitine cofactors and precursors may be lostthroughout the dialysis session (e.g., vitamin B6, niacin, vitaminC, lysine, and methionine). Due to a molecular weight gradient,the EC moieties are less likely to be filtered by the membranethan the FC, further impairing the abnormal serum EC/FC ratioalready present before end-stage renal disease.
The potential targets for administering L-carnitine in maintenancehemodialysis patients include: (1) dyslipidemia, because carnitineincreases mitochondrial transport of FFA and reduces FFA availabilityfor triglycerides synthesis; (2) muscle weakness, because ofa decreased muscle carnitine content; (3) cardiac symptoms,because the myocyte has one of the highest intracellular carnitineconcentrations of the body and myocardial ischemia generatesacylcarnitine products and intracellular lactate production;and (4) anemia for correcting numerous metabolic abnormalities(e.g., oxidative stress and impaired phospholipid turnover).A number of experimental studies have shown that administeringL-carnitine to depleted animals has potential benefits for myocardialfunction, muscle composition, and other various parameters.Since 1978, many trials have been conducted in human to evaluatethe effects of administering L-carnitine. Despite the fact thatnearly 2000 patients were included in more than 80 studies,it is still a matter of debate as to whether L-carnitine treatmentcan improve patient’s status and symptoms. We thereforeconducted a systematic review on the effects of L-carnitinetreatment in adult maintenance hemodialysis patients.
Trial Retrieval and Selection Processes
The trial search strategy was developed specifically for checkingelectronic databases (MEDLINE, Embase, LILACS, Cochrane Library)for clinical trials assessing the effects of L-carnitine supplementationin adult maintenance dialysis patients. We also searched therenal trials register of clinical trials, which was developedin-house after screening the above databases and including trialsobtained through the Cochrane Collaboration handsearching program.We had direct contacts with Sigma-Tau Laboratory, Italy, whokindly provided additional references of clinical trials addressingthe L-carnitine treatment issue. Articles not written in English,French, Italian, or Spanish language were translated into English.Authors of abstracts were contacted if the reported data werenot sufficient for analysis. Inclusion criteria were as follows:random allocation of treatment, control group receiving a placeboor no treatment, clinical outcome, or laboratory parametersrelevant to end-stage renal disease condition. Crossover trialswere also included if the order for administering L-carnitinewas randomly chosen at the start of the study and the data forthe first crossover period only was available. Nonrandomizedtrials, e.g., controlled clinical trials in which the treatmentwas not randomly allocated, prospective uncontrolled trials,and retrospective trials were excluded from analysis (see Table 1for selected trials). The study quality was systematicallyassessed in an open fashion at the time of data collection.
Table 1. Randomized controlled trials evaluating the effects of L-carnitine treatment in maintenance dialysis patients
Statistical Analyses
Data were pooled using the Hedges and Olkin method designedfor quantitative data (33). To allow their pooling, the resultsof each study were converted into an effect size (standardizeddifference). Providing heterogeneity was not present, the datawere pooled according a simple fixed-effect model. An overalltreatment effect size was calculated as the average of the resultof each study weighted to the inverse of its variance. The ratioof the overall effect size to its SD was used to test the probabilityof the null hypothesis, assuming a normal distribution of theeffect sizes. When a significant heterogeneity was detected,a method using a random model effect also described by Hedgesand Olkin was used (33). In this case, the confidence interval(CI) of the overall effect size is larger than the one obtainedwith a fixed model. The effect measure used was the differencebetween carnitine and control (placebo or no treatment) of thechange from baseline. The differences in changes were standardizedby dividing by the pooled intersubject SD. A negative effectsize indicates a greater change in the treated group as comparedwith the control group. If the SD or the standard error of thechange from baseline was not reported, it was calculated usingseveral methods. If the individual data were given, the varianceof the change was computed directly. If individual data werenot given, the variance was derived from the P or the T valueof the t test. When the exact P value was not given, the mostconservative value was used (i.e., P = 0.0099 for P < 0.01).If the variance of the change could not be calculated, thiswas taken to be twice the variance of the measure. This lastestimation ignores the covariance, and thus the variance ofthe change is overestimated. All these methods lead to a conservativeestimate of the treatment effect, preventing a false positiveoverall treatment effect.
The Cochran Q test for homogeneity was performed. If no heterogeneitywas detected, an overall treatment effect size was calculatedfor each outcome, with the results of each study being weightedto the inverse of its variance (corresponding to a fixed effectmodel). If heterogeneity was detected (at a level of significanceof P < 0.10), a random effect model was used (33). All statisticsused two-tailed tests, with a threshold of statistical significanceof P 0.01.
From January 1978 to April 1999, a total number of 620 references,including "carnitine in title AND patients," were retrieved.From these, we identified 163 papers addressing the renal failurecondition. There was no provision of L-carnitine to patientsin 84 of them. L-carnitine was therefore administered to patientsin 79 published studies, of which 62 were not controlled (listavailable on request). Thus, only 17 published trials addressedthe effects of L-carnitine in a random and controlled manner(Table 1). We were able to identify four subsequent abstractsof studies also including a random administration of L-carnitine(Table 1). We then excluded from analysis three randomized trials(Mitwalli et al., 1999; Sloan et al., 1998; Trivelli et al.,1982, Table 1) because data available in these papers or aftercontacting the investigators were not suitable for analysisof selected criteria (data relevant to our analysis not recordedduring trial for one, no response after contacting authors forone, and quality of life estimation only for one). Finally,we analyzed data obtained from 18 trials and 482 patients (mean,27 patients per study; range, 10 to 82).
Effects of L-Carnitine Treatment on Serum Lipid Profile
As seen in Figures 1 and 2, the effects of L-carnitine on serumlipid profiles were variable, and no clear conclusions can bedrawn from the individual studies. Serum triglycerides variationswere compared between patients receiving L-carnitine and thosenot receiving L-carnitine in nine trials (Figure 1). Five trialsshowed nonsignificant serum triglycerides changes, whereas fourreported significant variations between treated and controlpatients, two being in favor of L-carnitine supplement and twoagainst L-carnitine. It should be noted that the size of thesetrials was probably too small to provide a sufficient statisticalpower. Despite improving statistical power by increasing thepatient number to 250, no statistically significant change inserum triglycerides profile was observed. The meta-analysisshowed an overall effect size of 0.11, which suggests a nonsignificantincrease in serum triglycerides (P = 0.81; n = 250). The carnitineeffect was heterogeneous between studies, and this was stillpresent after the use of a random effect model (P heterogeneity< 0.01; e.g., Cochran Q test on Figure 1[H]).
Figure 1. The effect of L-carnitine on serum triglycerides (top; random model analysis) and on total cholesterol (bottom; fixed model analysis). Open boxes indicate the effect of each individual trial, and the closed boxes the overall effect of treatment. The P value is given for overall treatment effect and is significant for values 0.01. Heterogeneity of treatment effect among trials is present if H test value is < 0.10.
Figure 2. The effect of L-carnitine on serum cholesterol fractions (top, VLDL; middle, LDL; bottom, HDL [fixed model analysis]). Open boxes indicate the effect of each individual trial, and the closed boxes the overall effect of treatment. The P value is given for overall treatment effect and is significant for values 0.01. Heterogeneity of treatment effect among trials is present if H test value is < 0.10.
The changes in serum cholesterol fractions were analyzed fromnine studies. Total serum cholesterol variations were obtainedin all nine studies (Figure 1), whereas HDL-cholesterol changeswere available from eight studies, LDL-cholesterol from fivestudies, and VLDL-cholesterol in only three trials (Figure 2).Again, there was no significant change in any of the individualtrials. The overall changes obtained by pooling the data werenot statistically significant for serum total cholesterol orfor any of its fractions (Figures 1 and 2). No heterogeneitywas observed (P heterogeneity > 0.1; Figures 1 and 2).
Effects of L-Carnitine Treatment on Anemia and Erythropoietin Requirement
Before the introduction of recombinant human erythropoietin(EPO), some studies assessed the effects of L-carnitine on patients’hemoglobin or hematocrit levels. The hemoglobin levels increasedin the groups receiving L-carnitine as compared with the groupsnot receiving L-carnitine (Figure 3). When pooled, these threestudies resulted in a statistically significant common sizeeffect of 0.50 (P < 0.01; Figure 3). This size effect indicatesthat a patient in the 50th percentile of hemoglobin level distributionin the placebo group would reach the 70th percentile if treatedby L-carnitine. Although this does not indicate a 20% increasein hemoglobin level, this improvement is clinically significant.No statistically significant heterogeneity was detected (P heterogeneity= 0.20; Figure 3).
Figure 3. The effect of L-carnitine on anemia control (top; fixed model analysis) and erythropoietin dose reduction (bottom; random model analysis). Open boxes indicate the effect of each individual trial, and the closed boxes the overall effect of treatment. The P value is given for overall treatment effect and is significant for values 0.01. Heterogeneity of treatment effect among trials is present if H test value is < 0.10.
Recombinant human EPO became available in 1989. We identifiedsix randomized trials addressing the question of whether itwas possible, by providing L-carnitine, to reduce the EPO dosewhile maintaining a constant hemoglobin or hematocrit level(Figure 3). A reduction in EPO dose was achieved in the carnitine-treatedgroups in five of the six studies while maintaining a comparabletarget hemoglobin in both the carnitine and control groups.The EPO dose was significantly smaller as compared with thecontrol groups in four trials (Figure 3). A common effect sizeof -0.75 (random effect model) was observed, with a statisticallysignificant level of heterogeneity (P heterogeneity = 0.02).This indicates that a patient in the 50th percentile of EPOdose distribution in the placebo group would reduce his/herEPO dose to the 23rd percentile if treated by L-carnitine. Theeffects of L-carnitine supplements between trials were, however,heterogeneous; therefore, the conclusion appears less robust.
Figure 4 shows the EPO resistance index (ERI), as defined bythe EPO dose given per gram of hemoglobin to maintain a constanthemoglobin (or hematocrit) level (22,34). We were able to calculatethis index in four trials only. In the control groups, therewas no change in EPO dose and no variation in hemoglobin levels,resulting in an unmodified ERI (Figure 4, left). By contrast,in the carnitine-treated groups, the ERI decreased in threeof the four studies, in favor of an improvement in this index(Figure 4, right).
Figure 4. The effect of L-carnitine on erythropoietin resistance index (ERI) in control (left) and L-carnitine–treated (right) groups. ERI was defined as the ratio of the EPO dose divided by the patients hemoglobin level. Data were available in four trials.
Effects of L-Carnitine Treatment on Myocardial Function, Arrhythmia, Asthenia, and Exercise Capacity
Other frequent symptoms related to maintenance dialysis havealso been examined as potential targets for L-carnitine adjuvanttreatment: myocardial function (7,17), arrhythmia (17), astheniaand fatigue (4,13,15), exercise capacity, and muscle weakness(1,9,13,14). However, after careful analysis of individual trials,data were not combinable because most of these trials used heterogeneousdesign or assessment methods that have been poorly or not validatedin dialysis patients.
There are compelling indicators of carnitine loss and/or deficiencyin maintenance dialysis patients as a result of low dietaryintakes and increased losses during the dialysis procedure (29,35).However, restoring serum or tissue carnitine levels may notbe sufficient to correct the patients’ symptoms; therefore,the efficacy of L-carnitine administration should be assessedthrough good quality clinical trials with adequate clinicaloutcome measures. The present results are from an exploratorymeta-analysis, because no specific hypothesis was defined beforeanalysis. Therefore, the results can only suggest treatmenteffects but not demonstrate them. Other general limitationsare the overall small number of patients in the individual trialsand the limited number of double blind designed studies, leavinga potential investigator bias (Table 1). Other types of biasesmay have occurred that should be discussed. Publication bias,which is the consequence of negative studies rejected for publication,may reinforce the weight of positive published studies (36,37).We did not observe for any parameter analyzed a more importantweight of studies that included a larger number of patients,which may have a greater chance to be published. The fact thatwe chose to analyze only randomized trials, although leadingto a dramatic reduction in trials selection, protects againsta well-described artificial increase in treatment effect estimatein response to investigators biases and bad quality clinicaltrials (38). Finally, language bias may have been reduced byincluding trials in Italian and Korean language and searchingLILACS, the South American Spanish clinical trial database.
We were not able to find any significant effect of L-carnitinesupplementation on serum lipid profile in maintenance dialysispatients. The effect of L-carnitine on triglycerides was heterogeneousin the nine trials included (Figure 1), whereas the effectson total cholesterol (Figure 1) or its fraction (Figure 2) werenot heterogeneous, despite a smaller number of trials. Thisheterogeneity could be explained by differences in baselinelevels of triglycerides, dose-ranging effects, or center orpopulation effects. Opposite to the expectation, there was atrend for an overall increase in serum triglycerides, even thoughthe results were not statistically significant (Figure 1). Therisk difference observed for the LDL cholesterol fraction provideda P value of 0.06 (Figure 2) but was not considered significantbecause of the exploratory approach and multiple comparisontests with an increased risk of type I error. To further clarifythis point, we suggest that an additional adequately sized trialshould be performed. To date however, these results suggestthat L-carnitine supplementation may not be efficacious forcontrolling the renal failure–induced dyslipidemia, particularlywhen compared with other currently approved medications.
Before erythropoietin (EPO) became available in 1989, the factthat L-carnitine administration could improve the patients’anemia status was already noticed (39). In the present review,we identified three randomized controlled trials performed inthe pre-EPO era, of which two showed a statistically significantfavorable effect of L-carnitine supplement on hemoglobin level(Figure 3), although these trials included only a low numberof patients (Table 1). After 1989, the favorable effect of L-carnitineon red cells were confirmed by analyzing randomized trials inwhich L-carnitine was administered concomitantly with EPO (Figure 3).In these more recent studies, the purpose was to maintaina comparable hemoglobin or hematocrit level in both groups byprogressively reducing the EPO dose in the carnitine group.We used the erythropoietin resistance index (ERI) to expressthe body response to L-carnitine, i.e., the ratio of the EPOdose divided by the patient’s hemoglobin level. Any increasein hemoglobin or decrease in EPO dose during the study wouldinduce a reduction in this index. Figure 4 expresses the percentdecrease in ERI in both groups available in four trials. Thisindex was reduced by L-carnitine supplement (Figure 4, right),suggesting that L-carnitine improves erythropoietin efficiencyas compared with control groups (Figure 4, left). Together withthe previous observation of improved anemia before the EPO era(Figure 3), these findings suggest a beneficial effect of L-carnitinesupplement on anemia control in maintenance hemodialysis patients.Whether those effects are constant in all patients should befurther explored. Indeed, Caruso et al. (20) showed no overalleffect of L-carnitine on hemoglobin level after 6 mo of treatmentin their entire population, but patients older than 65 yr receivingcarnitine needed a lower EPO dose to maintain their hematocritlevel 3 mo after the end of trial, compared with elderly patientsnot receiving L-carnitine (20). Finally, we were not able tofind a dose-response pattern, and we did not observe a timelag for this beneficial effect. However, the number of patientswas limited, and larger studies will be needed to clarify thisimportant clinical point.
In this meta-analysis, we were not able to reliably assess theeffects of L-carnitine treatment on exercise capacity or cardiovascularinstability, because there was a large heterogeneity for definingand recording these clinical symptoms, preventing any poolingof data. Some trials used V02 max while others used a subjectiveassessment with different scales, most of which have not beenvalidated for use in chronic renal failure patients. Informationshould therefore be obtained from future good quality, well-designedtrials.
The results of this meta-analysis justify a new randomized controlledtrial to evaluate the utility of adjuvant L-carnitine treatmentfor anemia management in hemodialysis patients (40). On thebasis of this meta-analysis, 260 patients should be enrolledto reach the statistical power to observe a reduction of 20%in the EPO dose from a weekly dose of 6000 ± 3000 IU.Cost-benefit analysis should include the estimation of moneyspared by the achieved reduction in EPO dose and the additionalL-carnitine expenses. The route of administration of L-carnitineshould also be assessed because there is no evidence from clinicaltrials as to the most efficient method of L-carnitine administrationin maintenance hemodialysis patients.
Footnotes
The present affiliation of Dr. Hurot is Centre de Rein Artificiel,Tassin, France
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Received for publication January 11, 2001.
Accepted for publication August 23, 2001.
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45(4):
729 - 735.
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Abstract
Introduction
0.01. 
