L-Carnitine in Dialysis Patients

Suhail AhmadScribner Kidney Center and the Department of Medicine, University of Washington, Seattle, Washington

ABSTRACT

Hemodialysis (HD) patients often have low serum concentra-tions of free L-carnitine and decreased skeletal muscle stores. AsL-carnitine is an essential cofactor in fatty acid and energy me-tabolism, it is possible that abnormal carnitine metabolism indialysis patients may be associated with clinical problems suchas skeletal myopathies, intradialytic symptoms, reduced cardiacfunction, and anemia. Studies have shown that L-carnitinesupplementation in HD patients improves several complicationsseen in dialysis patients, including cardiac complications (ar-rhythmias, reduced output, low cardiothoracic ratio), limitationof exercise capacity, increased intradialytic hypotension, and

muscle symptoms. The most promising results have been notedin the treatment of erythropoietin-resistant anemia. Routine ad-ministration of L-carnitine to all dialysis patients is not recom-mended at this time; however, a therapeutic trial of L-carnitinecan be useful in symptomatic patients with certain clinical fea-tures unresponsive to the usual measures. These include intra-dialytic muscle cramps and hypotension, asthenia, cardiomyop-athy, lowered ejection fraction, muscle weakness or myopathy,reduced oxygen consumption, and anemia requiring large dosesof EPO.

L-carnitine is a naturally occurring compound thatshuttles fatty acids into the cellular mitochondria forboxidation. It is crucial for energy production in tissuesdependent on fatty acid oxidation, for example, cardiacand skeletal muscles. In fact, more than 90% of bodycarnitine is found in skeletal and cardiac muscle (tissueconcentrations of L-carnitine range from 2000to 4600mM in the muscle and 3500 to 6000mM in theheart to just 200 to 500mM in the brain) (1). Cellscontain both free carnitine and a spectrum of carnitineesters (acylcarnitines). The distribution of the total car-nitine (TC) pool between free carnitine and acylcarni-tines has a direct impact on cellular energetics. L-carnitine decreases the intramitochondrial ayl-CoA:CoAratio. In cases of L-carnitine insufficiency, the acyl moi-eties accumulate, binding to the CoA and increasing theratio of acyl to free CoA. This inhibits key enzymesinvolved in energy production by the cell (2). Carnitine issynthesized mainly in the liver, brain, and kidneys; meatand dairy products are rich dietary sources (3). L-carnitine stores are repleted from diet and biosynthesis.

Renal Handling of Carnitine

The kidney has an important effect on the metabolismof carnitine. In healthy individuals, carnitine is freelyfiltered and tubular resorption of free carnitine (FC) isalmost complete; what appears in urine is carnitine ester,or acylcarnitine (AC). Thus in normal individuals therenal clearance of AC is four to eight times that of FC

(4–6). Deteriorating renal function is associated with de-creased carnitine clearance and impairment of normalexcretion of AC, leading to elevated plasma levels ofcarnitine. Thus uremic patients who are not yet on di-alysis have increased levels of both FC and TC andmarkedly elevated concentrations of AC (5).

Carnitine in Hemodialysis Patients

Unlike nondialyzed uremic patients, most hemodialy-sis (HD) patients exhibit relative carnitine deficiency,which is manifested as subnormal plasma/serum FC con-centrations (5, 7–13) and diminished muscle stores (6,14–19). As with uremic patients, HD patients have mark-edly elevated AC levels (5, 8, 10, 12) (Fig. 1). HD pa-tients demonstrate an abnormally high ratio of aryl tofree carnitine (5, 9, 10, 13, 20). An AC:FC ratio ofgreater than 0.40 indicates a relative FC deficiency (in-sufficiency); in normal patients the AC:FC ratio is ap-proximately 0.19, while it is increased to 0.87 in HDpatients (21). Despite the abnormal carnitine fractions,most investigators report that the plasma concentrationof TC in HD patients is normal (5, 10, 12, 18, 22) ordecreased (8, 14, 19, 22, 23), whereas three investigatorshave reported elevated TC levels in HD patients (6). Thepossible reasons for subnormal FC concentrations areincluded in Table 1.

Dialytic Losses

Carnitine is a small water soluble molecule that is welldialyzed; during one HD session, plasma concentrationsof carnitine declined as much as 75% (24). This rapiddecrease is quickly corrected by transport of carnitinefrom tissue stores, which may lead to a decrease inmuscle carnitine levels (18, 20). One study showed thatmuscle carnitine content 6 hours after HD remained

Address correspondence to: Suhail Ahmad, MD, ScribnerKidney Center, University of Washington, Department ofMedicine, 2150 North 107th St., Suite 160, Seattle, WA 98133.Seminars in Dialysis—Vol 14, No 3 (May–June) 2001 pp.209–217

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lower than predialysis concentrations (25). Plasma levelsof TC return to predialysis levels 6 hours after HD (18).Although most investigators report that the TC lost dur-ing dialysis per week is similar to weekly urinary carni-tine excretion in normal individuals, FC clearance by HDis greater than that of AC, a pattern that is the reverse ofnormal urinary carnitine excretion (20), which may con-tribute to decreases in FC concentration.

Dialysis Vintage

L-carnitine deficiency progresses with dialysis vintage(duration of dialysis); significant negative correlation hasbeen found between dialysis duration (vintage) andplasma FC concentration (Fig. 2) (26, 27), as well asbetween months on dialysis and muscle carnitine content(Fig. 3) (16). Bazzi et al. (25) found that patients under-going HD for more than 10 years had decreased musclecarnitine; this was not seen in patients who had been on

HD for less than 3 years (25). Significant reductions inpredialysis TC levels with dialysis vintage have beendocumented as well. Over a 25-week period, Rodriguez-Segade et al. (28) found a gradual decrease in serum TClevels, and Kudoh et al. (7) documented a gradual reduc-tion in predialysis plasma TC levels over a 2-year period;however, this was not a consistent finding. Older patientsappear to be at greatest risk for carnitine deficiency; thereis a significant negative correlation between serum FClevels and age (27). There appears to be no relationshipbetween carnitine deficiency and measures of dialysisadequacy (27).

Fatty Acid Abnormalities

Fatty acid metabolism and the distribution of fattyacids are abnormal in dialysis patients (29). Supplemen-tation with carnitine tends to normalize fatty acid pro-files. It is possible that because of abnormal fatty acidmetabolism the need for carnitine increases, and the rela-tive lack of FC (secondary to dialytic losses) may furthercontribute to the abnormal carnitine profile.

Peritoneal Dialysis

There are conflicting reports regarding the carnitineprofile in continuous ambulatory peritoneal dialysis(CAPD) patients. Virtually all studies report that CAPDpatients have normal TC levels in plasma (12, 18, 23,30–32). One study showed that muscle TC content wasnormal in CAPD patients (18). As is true in states ofchronic uremia and hemodialysis, CAPD patients havesignificantly elevated AC levels. Weekly losses of car-nitine in patients on CAPD or intermittent peritonealdialysis do not exceed urinary excretion rates in healthycontrols (12). Wanner and Ho¨rl (12) found normal oronly slightly decreased concentrations of FC in CAPDpatients. However, four groups of investigators have re-ported significantly lower FC values in CAPD patients(30, 32–34) (Table 2). Constantin-Teodosiu et al. (32)found the daily cumulative (renal plus peritoneal) loss ofFC (principally via peritoneal dialysis fluid) was 1.7-foldgreater in CAPD patients than the renal loss in healthycontrols, and Pliakogiannis et al. (33) observed a signifi-cant reduction in mean TC and FC levels in patients withdecreased protein levels compared to those with normalprotein status. Another investigator reported that plasma

FIG. 1. Plasma carnitine profile in HD patients and normal ranges.Values for total carnitine, free carnitine, acylcarnitine, and the ratio ofacyl to free carnitine are shown (mean ± standard error of the mean)(21).

FIG. 2. Correlation between dialysis vintage and free carnitine levelsin 107 patients on HD. Each point represents an individual patient (26).

TABLE 1. Potential factors contributing to carnitine depletionin HD patients

Decreased availability Increased requirements

Low dietary intake of carnitine-richfood (meat and dairy products)

Abnormal fatty acidmetabolism

Decreased endogenous production ofcarnitine

Nonselective dialytic losses (FC and AC)

FIG. 3. Correlation between dialysis vintage and muscle carnitinelevels in patients on HD. Each point represents an individual patient(16).

210 Ahmad

carnitine concentrations were normal during the firstyear of CAPD, but declined progressively during thesecond year of therapy (30). It may be that there is anincreased loss of FC and AC in the peritoneal fluid orthat plasma FC is exchanged for AC in the liver (32).

Clinical Features of Carnitine Deficiency

Dialysis patients suffer from many complicationswhich are similar to those observed with carnitine defi-ciency. Several studies have evaluated the possible clini-cal consequences of abnormal carnitine metabolism inHD patients.

Skeletal Myopathies

Skeletal myopathies associated with abnormal carni-tine metabolism include muscle weakness, fatigue,cramps/aches, and abnormal histology. These are com-mon complaints in HD patients; intradialytic musclecramps may occur in as many as 86% of patients (35).HD patients with muscle symptoms exhibit a signifi-cantly lower level of FC (Fig. 4A) and a higher AC:FCratio (Figure 4B) than those without symptoms (26).

Exercise Performance

HD patients have severely limited exercise capacityand a low peak oxygen consumption. These limitations

are seen even in those patients with normal cardiac andpulmonary function and normal hematocrit, suggestingthat the defect is at the level of skeletal muscle (3). Alinear regression study showed a positive correlation be-tween endogenous muscle carnitine content and maximalexercise capacity in HD patients (Fig. 5); exercise dura-tion was reduced by 50% in carnitine-deficient patients(16).

Cardiac Dysfunction

Cardiovascular disease is a significant cause of mor-bidity and accounts for as many as 50% of deaths indialysis patients (36). Patients on HD typically havemany risk factors associated with poor cardiac function,including anemia, hypertension, lipid abnormalities, andfluid excess (13, 37, 38).

Evidence for the relationship between carnitine andcardiac function in ESRD patients is circumstantial. It iswell established that inherited systemic carnitine defi-ciency (non-ESRD) causes familial cardiomyopathy (39,40); studies have also shown subnormal levels of FC inischemic heart disease and heart failure (2, 41). Second-ary carnitine deficiency is associated with dialysis-resistant cardiomegaly; a multiregression analysis foundthat plasma free carnitine levels in patients on chronicHD were markedly reduced and inversely correlated withcardiothoracic ratio (Fig. 6) (7). In addition, a linear re-gression study found a significant association betweenlow FC concentration and reduced ejection fraction (Fig.7) (13).

Intradialytic Complications

One of the most common complications during HD ishypotension. Riley et al. (27) found significantly lowerserum levels of TC and FC in well-dialyzed HD patientswith intradialytic hypotensive episodes (a decrease ofmore than 15 mm/Hg) compared to HD patients withoutthese episodes (Table 3) (27).

Rehabilitation

Riley et al. (27) also found a significant correlationbetween a reduced Karnofsky score (an indicator of

TABLE 2. Abnormal blood carnitine levels (µmol/L) inCAPD patients

Freecarnitine

(FC)

Acylcarnitine(AC)

AC:FCratio

Totalcarnitine

(TC)

Normal values (33) 48 ± 112 6 ± 3 <0.4 57 ± 11Pliakogiannis et al.

(33) 30 ± 11a 14 ± 8 0.5 ± 0.3 44 ± 14Constantin-Teodosiu

et al. (32) 28 ± 1 9 ± 2 0.5 ± 0.1 43 ± 2Moriwaka et al. (34) 29b 15 0.5 43Buoncristiani et al.

(30) 28a Males: 35 ± 9; females: 26 ± 10.b For more than 5 years on CAPD, the FC level was 27.

FIG. 4. Difference in (A) free carnitine levels and (B) AC:FC ratio between HD patients with (n 4 30) and without (n 4 21) symptoms (26).

211L-CARNITINE IN DIALYSIS PATIENTS

functional status) and increased AC:FC ratio (Fig. 8).The low functional status in patients with reduced serumcarnitine levels may be linked to poor cardiac functionand/or poor muscle function.

Anemia

While the most important cause of anemia in dialysispatients is decreased erythropoietin (EPO), evidence is

mounting that carnitine also plays a role. Lower TC andFC levels have been found in HD patients with anemiacompared to those without. Kooistra et al. (42) found thatpatients with lower TC levels required higher EPO dosesto maintain a hematocrit of 30 or more (Fig. 9). A sig-nificant inverse correlation has also been reported be-tween FC levels and EPO dosage (43). These studiessuggest that carnitine deficiency contributes to anemiaand may be one of the causes of relative EPO resistance.

Carnitine Supplementation inHemodialysis Patients

More than 65 studies have evaluated L-carnitinesupplementation in HD patients using doses ranging

FIG. 5. Correlation between exercise capacity (peak exercise time onthe graded ergometer protocol) and muscle stores (total muscle carni-tine at rest) in HD patients. Each point represents an individual patient(16).

FIG. 6. Inverse correlation between plasma free carnitine levels andcardiothoracic ratio (on chest radiograph) in 33 HD patients. Each pointrepresents an individual patient (7).

FIG. 7. Correlation between ejection fraction and plasma free carni-tine levels in 16 HD patients. Each point represents an individualpatient. The overall left ventricular ejection fraction was determined bymultigated blood pool imaging using an in vivo labeling technique ofred blood cells with 1000 MBQ[99T]pertechnetate following adminis-tration of stannous pyrophosphate (13).

TABLE 3. Serum carnitine levels in patients with (n = 8) andwithout (n = 23) intradialytic hypotension

Without hypotension With hypotension

Total carnitine (TC)(mmol/L)

27.0 ± 2.7 18.4 ± 2.2a

Free carnitine (FC)(mmol/L)

18.8 ± 2.0 10.9 ± 1.7b

AC:FC ratio 0.58 ± 0.06 0.78 ± 0.15a p < 0.05.b p < 0.01.

FIG. 8. Relationship between Karnofsky Activity Scale score andacyl:free carnitine ratio (normal range < 0.40) in 30 HD patients. Eachpoint represents an individual patient (27).

FIG. 9. Relationship between required dose of rhEPO and total car-nitine levels in 16 HD patients with anemia who were in maintenancephase of treatment. Each point represents an individual patient (42).

212 Ahmad

from 5 to 100 mg/kg administered intravenously, orally,or via the dialysate. The majority of studies used intra-venous (IV) administration after each dialysis session. Amultitude of endpoints have been assessed. Treatment isassociated with significant increases in plasma concen-trations of all carnitine fractions (FC, AC, and TC).However, although the AC:FC ratio decreases duringtreatment, it is still markedly abnormal, even after 6months of supplementation (10). This suggests that theneed for FC by acyl moieties is high in these patients.

Cardiac Parameters

The myocyte has one of the highest intracellular con-centrations of carnitine in the body; metabolism in car-diac and skeletal muscle myocytes is largely oxidativeand depends on oxidation of fatty acids, which is influ-enced by carnitine. More than 15 studies have been re-ported in ESRD patients, and a number of them haveshown that supplementation with L-carnitine improvescardiac parameters in HD patients.

Cardiac Arrhythmia. Short-term trials with a lim-ited number of patients have shown that L-carnitine sig-nificantly improves arrhythmia in HD (44–46). All pa-tients in Suzuki’s (44) 2-month, open-label study hadventricular and supraventricular premature beats at leastonce on an electrocardiogram, and 65% of patients ex-perienced premature beats during HD; both the incidenceand severity of these intradialytic premature beats weresignificantly reduced by oral administration of 2 g L-carnitine daily for 4–8 weeks (44). Franco et al. (45)conducted a 2-month, controlled trial in 19 chronic HDpatients; the patients receiving 2 g IV L-carnitine weredivided into those with (n 4 7) and without (n 4 6)supraventricular arrhythmia and ventricular ectopic beatson 24-hour Holter monitor, including dialysis period. Astatistically significant reduction in the incidence of ar-rhythmia was shown in 40% of patients with arrhythmia(45). In Fricke’s controlled 2-month study of eight HDpatients with uremic cardiomyopathy who received 20mg/kg IV L-carnitine, a significant decrease in ectopicbeats was observed (46).

In our multicenter, double-blind, controlled, clinicaltrial, 82 maintenance HD patients were randomized toeither 20 mg/kg IV L-carnitine or placebo after eachdialysis session for 6 months. No significant change indialysis-associated arrhythmias was shown; however, thestudy had little power to detect such a change since therewere very few arrhythmias in the patients at baseline(47).

Cardiac Function. Left ventricular ejection frac-tion has been evaluated in HD patients receiving L-carnitine (13, 46, 48–50). In a 3-month, open-label studyof 16 patients receiving 1 g IV L-carnitine, a statisticallysignificant increase in ejection fraction was shown inpatients with lower ejection fraction (from 30.4 ± 16% to41.7 ± 15.9%,p < 0.02) (13). In another study, Khoss etal. (48) noted better left ventricular function after 6 (24%improvement) to 18 (44% improvement) months of L-carnitine treatment in children on HD (age 3.4–20 years);normalization of fiber-shortening velocity occurred after1 year of therapy. Improvement in cardiac function was

noted in two long-term HD patients supplemented withL-carnitine who had extremely low cardiac FC levels andsevere idiopathic cardiomyopathy (3).

No changes in ejection fraction were shown in threeshort-term (1.5–2 months) studies of adult L-carnitinerecipients on HD, although in two trials, other cardiacindices showed improvement (46, 49, 50). Fricke et al.(46) used carnitine to treat a group of eight chronic HDpatients and found no effect on left ventricular functionbut a significant decrease in cardiac arrhythmias.Sakurabayashi et al. (49) used oral carnitine 1 g/day for1 month followed by 0.5 g/day for 1 month and noticedno change in echocardiography but a normalization of123I-labeled b-methyl-p-iodophenyl-pentadecanoic(BMIPP) acid uptake. I-labeled BMIPP myocardial scin-tigraphy is a recently developed test of myocardial fattyacid metabolism (BMIPP, the free fatty acid analogue,when absorbed into the myocardium, forms BMIPP-CoAfor oxidation). Fagher et al. (50) conducted a 6-week,double-blind, controlled study in 28 HD patients whoreceived 2 g IV L-carnitine after each dialysis session.No effect of carnitine in left ventricular function wasfound; however, the average value of ejection fraction inthese patients was 62% at baseline (50). The more posi-tive results with longer duration of treatment suggest alonger treatment time may be needed. In addition, thegreatest benefit of carnitine is expected in patients withabnormal cardiac function.

In a 1-month, double-blind, parallel, placebo-controlled trial in 20 HD patients using 3–5 g oral car-nitine, the cardiothoracic ratio (as determined by chestradiograph) decreased in carnitine recipients (from52.2% ± 5.09 to 50.6% ± 4.92) while it remained un-changed in the placebo-treated group (49.6% versus49.8%). In addition, longitudinal cardiac diameter de-creased in the carnitine recipients (from 15.03 ± 1.21 to14.66 ± 1.09) while remaining unchanged in the placebogroup (15.9 versus 15.2). Carnitine supplementation wasassociated with an increase in plasma carnitine levels(from 41 mmol/L to 49 mmol/L) (51).

Dyspnea. A placebo-controlled, crossover trial con-ducted over 4 months showed highly significant attenu-ation of exertional dyspnea after 2 months of carnitinesupplementation (1.8 ± 2 to 0.1 ± 0.1). Dyspnea wasinversely proportional to the blood concentration of car-nitine; 60 days after discontinuation of carnitine, the in-cidence of dyspnea had risen to 75% of that of baseline(52). It was unclear whether the improvement in dyspneawas related to any other improvement in left ventricularfunction.

Skeletal Muscle Function

Numerous clinical trials have reported an improve-ment in skeletal muscle function in HD patients withL-carnitine supplementation (Table 4) (14, 25, 47, 52–61).

Muscle Strength and Mass. In our multicenter,controlled trial, IV L-carnitine was associated with anincrease in muscle mass; calculated midarm muscle areaimproved significantly in the L-carnitine group, whileplacebo recipients exhibited no change (47).

213L-CARNITINE IN DIALYSIS PATIENTS

Significant hypertrophy of type I and type IIa skeletalmuscles was reported in open-label studies in 48 HDpatients who received 2 g IV (n 4 33), oral (n 4 6), orthrough dialysate (n 4 11) L-carnitine for 6–12 months(52, 53, 56). The muscle fiber diameter decreased fol-lowing discontinuation of therapy (53).

In a 6-week, double-blind, placebo-controlled trial of2 g IV L-carnitine given three times a week, L-carnitinewas associated with significant improvement in maxi-mum muscle strength from baseline, although a signifi-cant difference from controls was not seen (58). Anincrease in total muscle power, as indicated by comput-erized electromyographic analysis, was shown in 20long-term HD patients who received 3 g IV L-carnitineafter dialysis for 7 months (59).

Exercise Capacity. Supplementation with L-carnitine improves exercise capacity, according to a va-riety of indices. In our large, controlled trial there was asignificant increase in peak oxygen consumption (mea-sured during a progressive work-exercise test) and atrend toward increased exercise time (47). Another long-term trial (6-month, double-blind, placebo-controlledtrial using 2 g IV L-carnitine after each dialysis) showeda trend toward improvement in muscle activity in allcarnitine-treated patients, with significant improvementshown in 60% of carnitine patients; in contrast, no sig-nificant change was observed in controls (54). A small,open-label study found a significant improvement inmaximum workload after 45 days of supplementationwith oral L-carnitine, which was sustained 60 days post-treatment (60).

Intradialytic Complications

Improvement in complications occurring during andjust after dialysis (hypotension, asthenia, and cramps) isassociated with increases in serum and muscle L-carnitine concentrations following L-carnitine supple-mentation (14, 52).

Hypotension. Several studies have shown a signifi-cant reduction in the incidence of intradialytic hypoten-sion with L-carnitine treatment. In our multicenter, con-trolled trial, the number of patients experiencing hypo-tensive episodes declined from 44% to 18% (p < 0.02) inthe carnitine-treated group, while the incidence in theplacebo group remained unchanged (47). Significant re-ductions in intradialytic hypotension were also reportedin an open-label study of 18 symptomatic HD patientswho had been on dialysis for an average of 7 years (61)and in a controlled crossover trial of 18 HD patients (52).A small study showed that 60% of HD patients had in-creased vascular refilling after L-carnitine therapy,which suggests that with L-carnitine there may be im-proved tolerance to ultrafiltration (62).

Muscle Cramps. Several controlled, double-blind,and open-label studies have shown that L-carnitinesupplementation in HD patients is associated with a de-crease in intradialytic and postdialytic muscle cramps(14, 26, 47, 52, 55, 56, 63). In our multicenter, controlledtrial, the incidence of muscle cramping decreased from36% to 13% following treatment with IV L-carnitine(47). Another double-blind, placebo-controlled trial ofIV L-carnitine in 30 HD patients showed improvement in43% of treated patients (55). Two double-blind, placebo-controlled crossover trials showed a significant improve-ment in muscle cramps in L-carnitine recipients that wasassociated with an increase in serum and muscle L-carnitine concentrations (14, 52). Open-label trials innearly 50 HD patients reported improvement in musclecramps in 60–100% of patients (26, 56, 63).

Weakness and Fatigue

Asthenia and fatigue are quite common in ESRD pa-tients. A number of studies have reported an improve-ment in asthenia and fatigue with carnitine treatment.However, these data are difficult to analyze because oftheir subjective nature. The duration of treatment in thesestudies ranged from 2 to 6 months; either IV or oralformulations were utilized in doses ranging from 20 mg/kg to 2 g/kg (14, 26, 47, 52, 63). Other controlled trialshave found significant improvements in asthenia in L-carnitine-treated patients compared to placebo recipients(14, 52). Dialysis-associated asthenia improved 15–30days after treatment and recurred once L-carnitine wasdiscontinued, although symptoms did not appear until upto 30 days after discontinuation, suggesting a carryovereffect of the supplementation (14). Significant improve-ments in weakness and fatigue have also been reported inopen trials (26,63).

One 6-week, controlled study found no improvementin subjective ratings of fatigue and other muscle symp-toms (cramps, general condition) in 14 patients treatedwith L-carnitine; however, these patients were in goodnutritional state without any evidence of carnitine defi-ciency (58). In our multicenter, controlled trial, similarimprovements in postdialysis asthenia occurred in bothL-carnitine and placebo recipients (47).

Patient Well-Being

Three double-blind, placebo-controlled trials assessedpatient well-being (subjective assessments) (47, 55, 64).In our multicenter, double-blind trial, 50% of L-carnitinerecipients were rated by investigators as showing signifi-cant improvement in global well-being, compared with18% improvement in the placebo group (47). In their2-month, randomized trial of 30 patients using IV L-carnitine (1–1.5 g), Sohn et al. (55) found that a signifi-cantly greater percentage of L-carnitine recipients (33%)reported improvements in clinical symptoms than pla-cebo patients (7%). In another large, controlled, cross-over clinical trial in 101 HD patients, Sloan et al. (64)administered oral L-carnitine (1 g before and after eachdialysis session) for 6 months to one-third of patients,

TABLE 4. Effects of L-carnitine supplementation on musclefunction in HD patients57

? Reduced muscle cramps? Improved exercise performance? Increased muscle strength and mass? Decreased asthenia and dyspnea? Increased peak O2 consumption

214 Ahmad

while another third alternated between a 3-month regi-men of carnitine and placebo (placebo recipients consti-tuted the last third). Using the Medical Outcomes StudyShort Form, they found significant improvements in per-ception of physical function and general health just 1.5months after treatment with L-carnitine; however, theperceived effect was not sustained at 6 months (64).

Lipid Abnormalities

Carnitine supplementation has not resulted in uniformimprovement in plasma lipids in dialysis patients (6, 10,11, 22, 44, 65–68). It is difficult to draw conclusionsfrom the data, as there are large variances in baselinelipid levels, sample size, study length, analytical meth-ods, dosage, and route of administration (2). A multiplelinear regression analysis of lipid-lowering therapies inpatients with renal disease weighted by study quality(factors included randomized, placebo-controlled,blinded, inclusion criteria) and inverse variance foundthat carnitine decreased total cholesterol and triglycer-ides, increased HDL, but had no effect on LDL (69). Ourmulticenter, controlled trial did not note any effect ofcarnitine on a comprehensive battery of lipid frac-tions (1).

Anemia

Several studies have shown that L-carnitine sig-nificantly improves chronic anemia in HD patients and/or reduces epoietin requirements (11, 14, 70–77). TheAmerican Association of Kidney Patients (AAKP) Con-sensus Group, the National Kidney Foundation (NKF),and a number of investigators recommend empiric treat-ment with L-carnitine in dialysis patients with EPO-resistant anemia (78–80). It is possible that, by modify-ing the fatty acid metabolism, L-carnitine stabilizes theerythrocyte membrane (which has an important lipidcomponent), thus increasing the life span of mature redblood cells (3, 70, 80) and lowering EPO requirements.Matsumura et al. (43) confirmed that red blood cellglobular osmotic fragility increased with low L-carnitinelevels. Kletzmayr et al. (70) found a significant negativecorrelation between plasma FC and TC levels and eryth-rocyte survival time and also found a significant asso-ciation between red blood cell survival time and EPOrequirements. Administration of L-carnitine has beenshown to reduce erythrocyte membrane fragility in HDpatients (81), although this is not confirmed by otherinvestigators (71).

Non-EPO-Treated Dialysis Patients. Increases inhematocrit (11, 14, 72, 74–77) and hemoglobin (74, 76,77) have been reported following L-carnitine supplemen-tation in non-epoetin-treated hemodialysis patients.Trovato et al. (74) observed an unusually large increasein hematocrit from 25.5% to 37.3% in carnitine recipi-ents after 1 year of high-dose oral carnitine. The durationof treatment appears to be important, since most of thestudies reporting an increase in hematocrit have beenrelatively long term (3). Studies of non-epoetin-treatedpatients receiving L-carnitine supplementation have

noted an increase in red blood cell count, which appearsafter 3 months of treatment (74, 76, 77).

Reduced EPO Requirements. EPO is routinelyadministered when hematocrit falls below 30% or hemo-globin falls below 10 g/dl. The NKF-DOQI Work Groupon Anemia Management recommends a target hemato-crit of 33–36% (79) and many experts suggest normal-izing hematocrit (82). Controlled trials show that IV L-carnitine improves the response to epoetin in HD patients(70, 71, 82). In a double-blind, placebo-controlled, clini-cal trial, Labonia et al. (71) found that IV L-carnitinesupplementation for 6 months reduced EPO require-ments by 38.1%. In another double-blind, controlled trialof IV L-carnitine, EPO requirements decreased 36.9% inresponders (8/19 patients). At baseline, the respondershad higher levels of carnitine in plasma and red bloodcells than the nonresponders. This suggests that higherplasma FC levels are necessary for the desired therapeu-tic effect and that severely carnitine-depleted patientsmight need a higher dose of L-carnitine for a longerperiod of time to reduce EPO dosage (70). In another6-month, double-blind, placebo-controlled study, supple-mentation with IV L-carnitine resulted in a significantreduction of EPO requirements in patients older than 65years. A greater benefit was observed in patients withlarger increases in plasma carnitine levels (82). Thesefindings are supported by the use of IV L-carnitine inopen trials (73, 83) and reports of improved EPO respon-siveness in refractory patients with low carnitine levels(84).

Recommendations

At present, routine administration of L-carnitine to alldialysis patients cannot be recommended. However,there are several clinical syndromes often seen in thesepatients that appear to respond to the use of L-carnitine.L-carnitine should be used in these clinical conditions(described below), provided that more traditional treat-ments are not effective.

Serum carnitine levels do not reliably predict whichHD patients can benefit from L-carnitine therapy. Plasmaand tissue carnitine concentrations are poorly correlated(6, 17, 20, 85) and a number of studies have showncarnitine deficiency in muscle in the face of normalplasma levels (6, 15, 17–19, 86). Moreover, one inves-tigator found clinical evidence of profound carnitine de-ficiency in one-fifth of patients despite normal musclestores (6).

Clinical efficacy has been reported in some HD pa-tients with normal FC levels, as well as those with sub-normal carnitine concentrations; for example, those withimpaired ejection fraction (13). Since routine tissue mea-surement is too invasive and is impractical, a pragmaticapproach should be undertaken wherein L-carnitinesupplementation is recommended on the basis of theclinical picture (6). Consensus groups and investigatorsrecommend a therapeutic trial of L-carnitine in symp-tomatic patients with certain conditions that are unre-sponsive to standard therapy (13, 78–80). These condi-tions include intradialytic muscle cramps and hypoten-

215L-CARNITINE IN DIALYSIS PATIENTS

sion, asthenia, skeletal muscle weakness or myopathy,cardiomyopathy, and anemia unresponsive to or requir-ing large doses of EPO.

The plasma profile of carnitine concentration can alsobe used as a guide—a subnormal level of free carnitineand an elevated ratio of acyl to free carnitine ($ 0.6) maybe an indication of a need for carnitine supplementation.Clearly more work is needed to further clarify this areaand further define the population of patients who wouldbenefit from carnitine supplementation.

Dosage Regimen

Both oral and IV L-carnitine supplementation increaseTC and FC as well as AC in HD patients (57). Thebioavailability of oral carnitine in healthy individualsranges from 5% to 18% (87, 88). Several factors areimplicated in this low oral bioavailability, including deg-radation of carnitine by bacteria in the gastrointestinaltract (88); moreover, bioavailability is an issue in dialysispatients because the intestinal absorption of carnitine isdecreased (1, 11). Poor compliance is a major problem indialysis patients, who are already taking numerous un-pleasant oral medications each day (4, 68). Several in-vestigators, including the AAKP Carnitine Renal Dialy-sis Consensus Group, recommend that L-carnitine be ad-ministered intravenously (4, 57, 78, 86). Intravenouslyadministered drugs are completely available (89),achieving higher peak plasma and FC concentrationsthan oral therapy. Moreover, IV administration has theadvantage of ensuring compliance in what, for many pa-tients, constitutes an empiric trial (4, 57). Oral adminis-tration is utilized in patients on peritoneal dialysis be-cause it is not practical to administer IV therapy in thesepatients. Nonprescription oral formulations of L-carnitine, such as those available in health food stores,are not recommended, as these products may fail to dis-integrate properly, have low consistency, and may con-tain considerably less carnitine than labeled (90).

Safety. L-carnitine is very well tolerated; even withhigh doses (up to 15 g/day), no major side effects havebeen reported (2). Mild gastrointestinal effects (nauseaand vomiting) and, less frequently, body odor may occur.Seizures have been reported in patients with or withoutpreexisting seizure activity. The use of D,L-carnitine isnot recommended because a myasthenia-like syndromehas been documented in uremic patients receiving it (91).

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